Siklus selDari Wikipedia bahasa Indonesia, ensiklopedia bebas

Siklus sel

Siklus sel adalah fungsi sel yang paling mendasar berupa duplikasi akurat sejumlah besar DNA di dalam kromosom, dan kemudian memisahkan hasil duplikasi tersebut hingga terjadi dua sel baru yang identik.[1]

Siklus sel yang berlangsung kontinu dan berulang (siklik), disebut proliferasi. Keberhasilan sebuah proliferasi membutuhkan transisi unidireksional dan teratur dari satu fase siklus sel menuju fase berikutnya. Jenjang reaksi kimia organik yang terjadi seyogyanya diselesaikan sebelum jenjang berikutnya dimulai. Sebagai contoh, dimulainya fase mitosis sebelum selesainya tahap replikasi DNA akan menyebabkan sel tereliminasi.

Jenjang reaksi yang terjadi pada siklus sel, sangat mirip dengan relasi substrat-produk dari sebuah lintasan metabolik. Produk dari sebuah jenjang reaksi akan berfungsi sebagai substrat pada jenjang berikutnya, demikian pula dengan laju reaksi jenjang yang pertama akan menjadi batas maksimal laju reaksi pada jenjang berikutnya.

Transisi antara jenjang reaksi ditentukan oleh lintasan pengendali ekstrinsik dan intrinsik yang terdiri dari beberapa cekpoin, sebagai konfirmasi selesainya reaksi pada suatu jenjang sebelum jenjang berikutnya dimulai. Kedua lintasan kendali dapat memiliki cekpoin yang sama.

Lintasan kendali instrinsik akan menentukan setiap tahap berjalan sebagaimana mestinya. Fasa S, G2 dan M pada sel mamalia dikendalikan oleh lintasan ini, sehingga waktu yang diperlukan untuk fase tersebut, tidak jauh bervariasi antara satu sel dengan sel lain.

Lintasan kendali ekstrinsik akan berfungsi sebagai respon terhadap kondisi di luar sel atau telisik defisiensi sel.

Defisiensi lintasan kendali intrinsik seringkali menyebabkan kanker. Penyimpangan pada protein yang mengendalikan cekpoin siklus fase sering ditemukan pada penderita kanker.

Daftar isi  [sembunyikan] 

1 Fasa pada siklus sel 2 Cekpoin pada siklus sel

o 2.1 Transisi G0 ke G1

o 2.2 Transisi ke fase So 2.3 Fasa S

3 Lihat pula 4 Referensi 5 Pranala luar

Fasa pada siklus sel[sunting | sunting sumber]

Gambar skematik fase siklus sel yang dikendalikan oleh enzim CDK.[2]

Pada sel prokariota yang tidak memiliki inti sel, siklus sel terjadi melalui suatu proses yang disebut pembelahan biner, sedang pada sel eukariota yang memiliki inti sel, siklus sel terbagi menjadi dua fase fungsional, fase S dan M, dan fase persiapan, G1 dan G2:[3]

1. Fasa S (sintesis)

Merupakan tahap terjadinya replikasi DNA. Pada umumnya, sel tubuh manusia membutuhkan waktu sekitar 8 jam untuk menyelesaikan tahap ini. Hasil replikasi kromosom yang telah utuh, segera dipilah bersama dengan dua nuklei masing-masing guna proses mitosis pada fase M.

2. Fasa M (mitosis)

Interval waktu fase M kurang lebih 1 jam. Tahap di mana terjadi pembelahan sel (baik pembelahan biner atau pembentukan tunas). Pada mitosis, sel membelah dirinya membentuk dua sel anak yang terpisah. Dalam fase M terjadi beberapa jenjang fase, yaitu:[4]

Profase, fase terjadinya kondensasi kromosom dan pertumbuhan pemintalnya. Pada saat ini kromosom terlihat di dalam sitoplasma.

Prometafase, pada fase ini sampul inti sel terlarut dan kromosom yang mengandung 2 kromatid mulai bermigrasi menuju bidang ekuatorial (piringan metafase).

Metafase. kondensasi kromosom pada bidang ekuatorial mencapai titik puncaknya

Anafase. Tiap sentromer mulai terpisah dan tiap kromatid dari masing-masing kromosom tertarik menuju pemintal kutub.

Telofase. Kromosom pada tiap kutub mulai mengalami dekondensasi, diikuti dengan terbentuknya kembali membran inti sel dan sitoplasma perlahan mulai membelah

Sitokinesis. Pembelahan sitoplasma selesai setelah terjadi oleh interaksi antara pemintal mitotik, sitoskeleton aktomiosin dan fusi sel,[5] dan menghasilkan dua sel anak yang identik.

3. Fasa G (gap)

Fasa G yang terdiri dari G1 dan G2 adalah fase sintesis zat yang diperlukan pada fase berikutnya. Pada sel mamalia, interval fase G2 sekitar 2 jam, sedangkan interval fase G1 sangat bervariasi antara 6 jam hingga beberapa hari. Sel yang berada pada fase G1 terlalu lama, dikatakan berada pada fase G0 atau “quiescent”. Pada fase ini, sel tetap menjalankan fungsi metabolisnya dengan aktif, tetapi tidak lagi melakukan proliferasi

secara aktif. Sebuah sel yang berada pada fase G0 dapat memasuki siklus sel kembali, atau tetap pada fase tersebut hingga terjadi apoptosis.Pada umumnya, sel pada orang dewasa berada pada fase G0. Sel tersebut dapat masuk kembali ke fase G1 oleh stimulasi antara lain berupa: perubahan kepadatan sel, mitogen atau faktor pertumbuhan, atau asupan nutrisi.

4. Interfase

Merupakan sebuah jedah panjang antara satu mitosis dengan yang lain. Jedah tersebut termasuk fase G1, S, G2.[6]

Cekpoin pada siklus sel[sunting | sunting sumber]

Aktivitas selular yang terjadi pada cekpoin, tidak dapat berlangsung tanpa enzim intraselular yang disebut CDK. Holoenzim CDK aktif terdiri dari sub-unit katalitik dan sub-unit kendali siklin. Tiap siklin disintesis pada tahap terkait dari fase siklus sel. Sebagai contoh, siklin E disintensis pada akhir fase G1 hingga awal fase S, sedangkan siklin A disintesis sepanjang interval fase S dan G2, dan siklin B disintesis sepanjang fase G2 dan M. Oleh sebab itu, sub-unit katalitik tidak dapat teraktivasi, hingga siklin yang diperlukan selesai disintesis.

Ikatan yang dibentuk antara sub-unit siklin dan sub-uni katalitik membutuhkan proses fosforilasi pada treonina oleh enzim lain yang disebut CAK, yang terdiri dari siklin H dan CDK7.

Regulasi yang lain adalah deaktivasi CDK oleh fosforilasi domain pengikat ATP oleh enzim kinase yang lain. Deaktivasi tersebut dapat diaktivasi kembali oleh fosfatase dari jenis CDC25. Keberadaan protein inhibitor CDK juga merupakan bentuk regulasi terhadap CDK. Satu jenis penghambat CDK termasuk p21CIP1, p27KIP1, dan p57KIP2; sedangkan jenis yang lain menghambat siklin D/CDK4 atau siklin-6 CDK, antara lain p16INK4, p15INK4B, p18INK4C, dan p19INK4D. Sintesis, aktivitas dan degradasi penghambat ini berada dalam regulasi yang merespon sinyal mitogenik dan antimitogenik, seperti sinyal parakrin dari TGF-β.

Regulasi terhadap CDK di atas menentukan kecepatan terpicunya transisi fase dalam siklus sel, setelah CDK teraktivasi, transisi ke fase berikutnya akan segera terjadi, walaupun jenjang reaksi pada fase berlangsung, belum selesai.

Transisi G0 ke G1[sunting | sunting sumber]Fasa transisi dari fase G0 ke fase G1 disebut fase prima atau fase kompetensi replikatif,[7] pada hepatosit, fase prima dipicu oleh sekresi sitokina IL-6 dan TNF-α oleh sel Kupfferyang menyebabkan hepatosit kehilangan sebagian massanya. Potensi proliferasi hepatosit setelah kehilangan sebagian massanya.[8]

Berbagai protein disintesis pada fase G1 setelah sel meninggalkan fase G0, beberapa ribosom baru dibuat untuk mempercepat sintesis protein.

Sejumlah protein yang dihasilkan berupa enzim untuk mengembalikan fungsi metabolik yang hilang saat sel berada pada fase G0, seperti enzim yang dibutuhkan untuk sintesisisoprenoid, zat yang diperlukan untuk aktivitas onkogen Ras dan sintesis poliamina, yang mempunyai banyak fungsi termasuk menyediakan ikatan ionik dengan asam nukleat. Onkogen Ras disintesis sebagai protein prekursor dan membutuhkan proses paska-translasi sebelum dapat menjadi aktif dan melakukan transformasi sel.

Enzim lain yang berperan dalam sintesis DNA, seperti timidina kinase, DNA polimerase dan histon juga dihasilkan ribosom pada fase G1.

Transisi ke fase S[sunting | sunting sumber]Transisi ke fase S dari fase G1 dikendalikan oleh dua buah cekpoin, yaitu "kompetensi" dan "restriksi" yang terletak sekitar 12 dan 2 jam sebelum fase S dimulai. Paling tidak diperlukan tiga faktor pertumbuhan untuk melewati dua cekpoin ini, yaitu PDGF, EGF dan IGF-1.

Pencerap faktor pertumbuhan merupakan protein kompleks yang terbentak seluas membran sel dengan domain yang dapat mengenali faktor pertumbuhan di dalam periplasmadengan sangat khusus. Ligasi yang terjadi dengan ligan akan menginduksi transmisi sinyal ke dalam sitoplasma melalui aktivasi enzim tirosina kinase. Sinyal sitoplasmik yang disebut "kurir sekunder", dapat berupa berbagai protein yang telah mengalami fosforilasi oleh enzim kinase, seperti molekul kecil inositol fosfatase dan AMP; atau ion, seperti Ca2+, H+, dan Zn2+; kemudian diteruskan oleh menuju inti sel. Di dalam inti sel, gen kemudian teraktivasi sebagai respon terhadap "kurir sekunder" ini.

Fasa S[sunting | sunting sumber]Pada eukariota, berbagai aktivator (bahasa Inggris: multiple points of origin) diperlukan sebagai persiapan untuk memasuki fase S guna melakukan replikasi DNA, pada prokariota, hanya terdapat aktivator tunggal.[9] Fasa S dimulai dengan terjadinya paparan pulsa (bahasa Inggris: pulse exposure) dengan [3H].timidina pada sel, kemudian terjadi paparan lanjutan (bahasa Inggris: chase procedure) non-radioaktif dengan timidina "dingin". Kedua prosedur tersebut menghasilkan beberapa titik replikasi yang mulai nampak terjadi pada beberapa kromosom pada rantai ganda DNA.

Pada titik replikasi, rantai ganda DNA memisahkan diri menjadi dua untai tunggal, sehingga nampak seperti garpu. Pada tiap untai, terjadi sintesis untai DNA yang baru, dengan dimulai oleh molekul primer, atau molekul oligonukleotida pendek, dan diikuti oleh molekul-molekul lain dengan enzim DNA polimerase, membentuk rantai ganda DNA yang baru.

Molekul primer itu disebut RNA primer, yang disintesis dengan enzim RNA polimerase atau dikenal sebagai enzim primase, dari RNA tertentu yang bersifat komplemen dengan salah satu area kromosom pada untai DNA. Primosom merupakan sebutan bagi seluruh kompleks yang berikatan dengan RNA primer.

Polimerisasi untai DNA yang baru bergerak dari tiap-tiap primosom pada titik 5' untai baru ke titik 3' untai baru.[10] Untai baru yang bergerak dengan arah dari titik 3' untai induk ke 5' untai induk disebut untai awal, sedang untai baru yang bergerak sebaliknya disebut untai akhir. Untaian DNA baru dari RNA primer hingga tepat sebelum RNA primer berikutnya disebut fragmen Okazaki, sesuai nama ilmuwan Reiji Okazaki yang pertama kali berhasil mengamati proses polimerasi pada replikasi DNA. Saat polimerasi untai DNA yang baru menyentuh RNA primer pada fragmen Okazaki berikutnya, aktivitas eksonuklease enzim DNA polimerase akan menghancurkan RNA primer pada fragmen tersebut untuk meneruskan untai polimernya hingga menyentuh untai polimer berikutnya, setelah itu enzim DNA ligase akan menyambung kedua untai polimer itu menjadi satu.[11] Titik 5' merupakan letak gugus 5' fosfat, sedang titik 3' merupakan letak gugus 3' OH dari molekul gula deoksiribosa.[12] Ikatan yang terjadi antara kedua gugus ini disebut ikatan fosfodiester.[13]

Polimerasi untai DNA yang baru terhenti hingga bagian ujung kromosom yang disebut telomer. Pada bagian ini, enzim telomerase akan menyambung untaian tersebut dengan deretan molekul RNA sebagai penanda antar kromosom.[14] Pada manusia, berkas yang disisipkan antar kromosom adalah TTAGGG. Penelitian terakhir menunjukkan bahwa rentang telomer pada manusia lambat laun menjadi lebih pendek dengan pertambahan usia, pengamatan ini membuahkan teori penuaan telomer yang masih diteliti hingga saat ini.

Referensi[sunting | sunting sumber]

1. ̂  (Inggris)Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter (2002). Molecular Biology of the Cell - An Overview of the Cell Cycle (4 ed.). Garland Science. ISBN 0-8153-3218-1. Diakses tanggal 2010-07-10.

2. ̂  (Inggris)Kufe, Donald W.; Pollock, Raphael E.; Weichselbaum, Ralph R.; Bast, Robert C., Jr.; Gansler, Ted S.; Holland, James F.; Frei III, Emil. (2003). Holland-Frei Cancer medicine - Figure 3.2. Dana-Farber Cancer Institute, Harvard Medical School Boston, Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Department of Radiation and Cellular Oncology, University of Chicago Hospital, Chicago

Tumor Institute, University of Chicago Chicago, University of Texas, MD Anderson Cancer Center, Houston, American Cancer Society, Derald H Ruttenberg Cancer Center, Mount Sinai School of Medicine New York (6 ed.) (Hamilton on BC Decker Inc.,). ISBN 1-55009-213-8. Diakses tanggal 2010-07-09.

3. ̂  (Inggris)Kufe, Donald W.; Pollock, Raphael E.; Weichselbaum, Ralph R.; Bast, Robert C., Jr.; Gansler, Ted S.; Holland, James F.; Frei III, Emil. (2003). Holland-Frei Cancer medicine - Proliferation. Dana-Farber Cancer Institute, Harvard Medical School Boston, Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Department of Radiation and Cellular Oncology, University of Chicago Hospital, Chicago Tumor Institute, University of Chicago Chicago, University of Texas, MD Anderson Cancer Center, Houston, American Cancer Society, Derald H Ruttenberg Cancer Center, Mount Sinai School of Medicine New York (6 ed.) (Hamilton on BC Decker Inc.,). ISBN 1-55009-213-8. Diakses tanggal 2010-07-09.

4. ̂  (Inggris)Tom Strachan, Andrew P Read (1999). Human Molecular Genetics. University of Newcastle, University of Manchester (2 ed.) (Wiley-Liss). p. Figure 2.10. Cell division by mitosis. ISBN 1-85996-202-5. Diakses tanggal 2010-08-10.

5. ̂  (Inggris)"Animal cell cytokinesis.". Research Institute of Molecular Pathology; Glotzer M. Diakses tanggal 2011-06-11.

6. ̂  (Inggris)Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter (2002). Molecular Biology of the Cell - Interphase (4 ed.). Garland Science.ISBN 0-8153-3218-1. Diakses tanggal 2010-07-10.

7. ̂  (Inggris)"Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration". Department of Pathology and Laboratory Medicine, Brown University,; Fausto N, Laird AD, Webber EM. Diakses tanggal 2010-07-30.

8. ̂  (Inggris)"The role of cytokines in liver failure and regeneration: potential new molecular therapies.". The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Hospital,; Galun E, Axelrod JH. Diakses tanggal 2010-07-30.

9. ̂  (Inggris)Anthony JF Griffiths, Jeffrey H Miller, David T Suzuki, Richard C Lewontin, and William M Gelbart (2000). An Introduction to Genetic Analysis. University of British Columbia, University of California, Harvard University (7 ed.) (W. H. Freeman). p. Mechanism of DNA replication. ISBN 0-7167-3520-2. Diakses tanggal 2010-08-15.

10. ̂  (Inggris)Anthony JF Griffiths, Jeffrey H Miller, David T Suzuki, Richard C Lewontin, and William M Gelbart (2000). An Introduction to Genetic Analysis. University of British Columbia, University of California, Harvard University (7 ed.) (W. H. Freeman). p. Figure 8-30. The overall structure of a growing fork (top) and steps in the synthesis of the lagging strand. ISBN 0-7167-3520-2. Diakses tanggal 2010-08-16.

11. ̂  (Inggris)Anthony JF Griffiths, Jeffrey H Miller, David T Suzuki, Richard C Lewontin, and William M Gelbart (2000). An Introduction to Genetic Analysis. University of British Columbia, University of California, Harvard University (7 ed.) (W. H. Freeman). p. Figure 8-29. The reaction catalyzed by DNA ligase (Enz) joins the 3′-OH end of one fragment to the 5′ phosphate of the adjacent fragment. ISBN 0-7167-3520-2. Diakses tanggal 2010-08-16.

12. ̂  (Inggris)Anthony JF Griffiths, Jeffrey H Miller, David T Suzuki, Richard C Lewontin, and William M Gelbart (2000). An Introduction to Genetic Analysis. University of British Columbia, University of California, Harvard University (7 ed.) (W. H. Freeman). p. Figure 1-4. The fundamental building blocks of DNA. ISBN 0-7167-3520-2. Diakses tanggal 2010-08-16.

13. ̂  (Inggris)Anthony JF Griffiths, Jeffrey H Miller, David T Suzuki, Richard C Lewontin, and William M Gelbart (2000). An Introduction to Genetic Analysis. University of British Columbia, University of California, Harvard University (7 ed.) (W. H. Freeman). p. Genes as determinants of the inherent properties of species. ISBN 0-7167-3520-2. Diakses tanggal 2010-08-16.

14. ̂  (Inggris)Anthony JF Griffiths, Jeffrey H Miller, David T Suzuki, Richard C Lewontin, and William M Gelbart (2000). An Introduction to Genetic Analysis. University of British Columbia, University of California, Harvard University (7 ed.) (W. H. Freeman). p. Figure 8-33. ISBN 0-7167-3520-2. Diakses tanggal 2010-08-16.

Cell cycleFrom Wikipedia, the free encyclopedia

For the separation of chromosomes that occurs as part of the cell cycle, see mitosis. For the Academic journal, see Cell Cycle (journal).

See also: Cell division

Schematic of the cell cycle. outer ring: I =Interphase, M = Mitosis; inner ring: M = Mitosis, G1 =Gap 1, G2 = Gap 2, S = Synthesis; not in ring: G0 =Gap 0/Resting.[1]

Onion (Allium) cells in different phases of the cell cycle. Growth in an organism is carefully controlled by regulating the cell cycle.

The cell cycle or cell-division cycle is the series of events that take place in a cell leading to its division and duplication (replication) that produces two daughter cells. In prokaryotes which lack a cell nucleus, the cell cycle occurs via a process termed binary fission. In cells with a nucleus, as in eukaryotes, the cell cycle can be divided into three periods: interphase, themitotic (M) phase, and cytokinesis. During interphase, the cell grows, accumulating nutrients needed for mitosis, preparing it for cell division and duplicating its DNA. During the mitotic phase,

the cell splits itself into two distinct daughter cells. During the final stage, cytokinesis, the new cell is completely divided. To ensure the proper division of the cell, there are control mechanisms known as cell cycle checkpoints.

The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed. After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

Contents  [hide] 

1   Cell cycle phases o 1.1   G 0  phase o 1.2   Interphase

1.2.1   G 1  Phase 1.2.2   S Phase

o 1.3   Mitotic phase 2   Regulation of eukaryotic cell cycle

o 2.1   Role of cyclins and CDKs 2.1.1   General mechanism of cyclin-CDK interaction 2.1.2   Specific action of cyclin-CDK complexes

o 2.2   Inhibitors o 2.3   Transcriptional regulatory network o 2.4   DNA replication and DNA replication origin activity

3   Checkpoints 4   Role in tumor formation 5   See also 6   References 7   Further reading 8   External links

Cell cycle phases[edit]

State Description Abbreviation

quiescent/senescent

Gap 0 G0A resting phase where the cell has left the cycle and has stopped dividing.

InterphaseGap 1 G1

Cells increase in size in Gap 1. The G1   checkpoint    control mechanism ensures that everything is ready for DNA synthesis.

Synthesis S DNA replication occurs during this phase.

Gap 2 G2

During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2   checkpoint    control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.

Cell division

Mitosis M

Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.

G0 phase[edit]

Plant cell cycle

Animal cell cycle

The word "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence

occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; for example, become cancerous. Some cells enter the G0 phase semi-permanently e.g., some liver, kidney, stomach cells. Many cells do not enter G0 and continue to divide throughout an organism's life, e.g. epithelial cells.

Interphase[edit]Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during interphase. Interphase is a series of changes that takes place in a newly formed cell and its nucleus, before it becomes capable of division again. It is also called preparatory phase or intermitosis. Previously it was called resting stage because there is no apparent activity related to cell division.Typically interphase lasts for at least 90% of the total time required for the cell cycle.

Interphase proceeds in three stages, G1, S, and G2, preceded by the previous cycle of mitosis and cytokinesis. The cell's nuclear chromosomes are duplicated during S phase.

G1 Phase[edit]

The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called G1 (G indicatinggap). It is also called the growth phase. During this phase, the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate. The duration of G1 is highly variable, even among different cells of the same species. In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size.

S Phase[edit]

The ensuing S phase starts when DNA replication commences; when it is completed, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. During this phase, synthesis is completed as quickly as possible due to the exposed base pairs being sensitive to harmful external factors such as mutagens.

Mitotic phase[edit]Main article: Mitosis

The relatively brief M phase consists of nuclear division (karyokinesis). It is a relatively short period of the cell cycle. M phase is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These phases are sequentially known as:

prophase , metaphase , anaphase , telophase cytokinesis  (strictly speaking, cytokinesis is not part of mitosis but is an event that directly

follows mitosis in which cytoplasm is divided into two daughter cells)

Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei.[2] During the process of mitosis the pairs ofchromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell.[3] It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle – the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.

Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animals undergo an "open" mitosis, where the nuclear envelopebreaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces

cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.[4] Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.

Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called endoreplication. This occurs most notably among the fungi and slime moulds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.[5] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.

Regulation of eukaryotic cell cycle[edit]

Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.

Role of cyclins and CDKs[edit]

Nobel Laureate Paul Nurse

Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle.[6] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules.[7]Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especiallySaccharomyces cerevisiae;[8] genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g. cdc25 or cdc20.

Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylationthat activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.[9]

General mechanism of cyclin-CDK interaction[edit]This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2010)

Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. However, results from a recent study of E2F transcriptional dynamics at the single-cell level argue that the role of G1 cyclin-CDK activities, in particular cyclin D-CDK4/6, is to tune the timing rather than the commitment of cell cycle entry. [10]

Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell'sgenome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells.

Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.[11]

Specific action of cyclin-CDK complexes[edit]

Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (e.g. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (Rb). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S, which initiates the G2/M transition).[12] Cyclin B-cdc2 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.[9]

A recent quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells proposed an alternative model for interpreting the control of cell cycle entry. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment into cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression.[10]

Inhibitors[edit]

Overview of signal transduction pathways involved in apoptosis, also known as "programmed cell death".

Two families of genes, the cip/kip (CDK interacting protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor ofKinase 4/Alternative Reading Frame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.

The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor of β (TGF β), a growth inhibitor.

The INK4a/ARF family includes p16 INK4a , which binds to CDK4 and arrests the cell cycle in G1 phase, and p14 ARF  which prevents p53 degradation.

Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.[13]

Transcriptional regulatory network[edit]Current evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in Saccharomyces cerevisiae have identified 800-1200 genes that change expression over the course of the cell cycle.[8][14][15] They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated. [16]

Many periodically expressed genes are driven by transcription factors that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects. [17] Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression.[14][18] The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression).[15][19]

Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando et al. usedmicroarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type

cells and cells lacking all S-phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1 and S phase. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events.[15] Other work indicates that phosphorylation, a post-translational modification, of cell cycle transcription factors by Cdk1 may alter the localization or activity of the transcription factors in order to tightly control timing of target genes.[17][20][21]

While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded mRNA.[22]

DNA replication and DNA replication origin activity[edit]Analyses of synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes.[23] This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression,[24][25][26] and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

Checkpoints[edit]Main article: Cell cycle checkpoint

Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle.[27] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met. Checkpoints typically consist of a network of regulatory proteins that monitor and dictate the progression of the cell through the different stages of the cell cycle.

There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint. G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[9] An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.

p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints.

Role in tumor formation[edit]

A disregulation of the cell cycle components may lead to tumor formation.[28] As mentioned above, when some genes like the cell cycle inhibitors, RB, p53 etc. mutate, they may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugsor radiation.

This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle.[9]

The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.

In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S.

For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1.

The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural substances that protect cells from radiation damage and tend to be at their highest levels in S and at their lowest near mitosis.

See also[edit]

Synchronous culture  – synchronization of cell cultures Cellular model

References[edit]

1. Jump up ̂  Cooper GM (2000). "Chapter 14: The Eukaryotic Cell Cycle". The cell: a molecular approach (2nd ed.). Washington, D.C: ASM Press. ISBN 0-87893-106-6.

2. Jump up ̂  Rubenstein, Irwin, and Susan M. Wick. "Cell." World Book Online Reference Center. 2008. 12 January 2008 <http://www.worldbookonline.com/wb/Article?id=ar102240>

3. Jump up ̂  Maton, Anthea (1997). Cells: Building Blocks of Life. New Jersey: Prentice Hall. pp. 70–4. ISBN 0-13-423476-6.

4. Jump up ̂  De Souza CP, Osmani SA (2007). "Mitosis, not just open or closed". Eukaryotic Cell 6(9): 1521–7. doi:10.1128/EC.00178-07. PMC 2043359. PMID 17660363.

5. Jump up ̂  Lilly M, Duronio R (2005). "New insights into cell cycle control from the Drosophila endocycle". Oncogene 24 (17): 2765–75. doi:10.1038/sj.onc.1208610.PMID 15838513.

6. Jump up ̂  Nigg EA (June 1995). "Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle". BioEssays 17 (6): 471–80. doi:10.1002/bies.950170603. PMID 7575488.

7. Jump up ̂  "Press release". Nobelprize.org.8. ^ Jump up to: a  b Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB,

Brown PO, Botstein D, Futcher B (December 1998). "Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization".Mol. Biol. Cell 9 (12): 3273–97. doi:10.1091/mbc.9.12.3273. PMC 25624.PMID 9843569.

9. ^ Jump up to: a  b c d Robbins, Stanley L; Cotran, Ramzi S (2004). Vinay Kumar; Abul K Abbas; Nelson Fausto, eds. Pathological Basis of Disease. Elsevier. ISBN 81-8147-528-3.

10. ^ Jump up to: a  b Dong, P., Maddali, M.V., Srimani, J.K., Thelot, F., Nevins, J.R., Mathey-Prevot, B., and You, L. (2014). Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control. Nat Commun 5, 4750.

11. Jump up ̂  Mahmoudi, Morteza; et al. (January 2011). "Effect of Nanoparticles on the Cell Life Cycle". Chemical Reviews 111 (5): 3407–3432. doi:10.1021/cr1003166.

12. Jump up ̂  Norbury C (1995). "Cdc2 protein kinase (vertebrates)". In Hardie, D. Grahame; Hanks, Steven. Protein kinase factsBook. Boston: Academic Press. p. 184. ISBN 0-12-324719-5.

13. Jump up ̂  Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer Agents

14. ^ Jump up to: a  b Pramila T, Wu W, Miles S, Breeden L (August 2006). "The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle". Genes Dev 20 (16): 2266–227.doi:10.1101/gad.1450606. PMC 1553209. PMID 16912276.

15. ^ Jump up to: a  b c Orlando DA, Lin CY, Bernard A, Wang JY, Socolar JES, Iversen ES, Hartemink AJ, Haase SB (June 2008). "Global control of cell-cycle transcription by coupled CDK and network oscillators". Nature 453 (453): 944–947. Bibcode:2008Natur.453..944O.doi:10.1038/nature06955.

16. Jump up ̂  de Lichtenberg U, Jensen LJ, Fausbøll A, Jensen TS, Bork P, Brunak S (April 2005)."Comparison of computational methods for the identification of cell cycle-regulated genes". Bioinformatics 21 (7): 1164–1171. doi:10.1093/bioinformatics/bti093.PMID 15513999.

17. ^ Jump up to: a  b White MA, Riles L, Cohen BA (February 2009). "A systematic screen for transcriptional regulators of the yeast cell cycle". Genetics 181 (2): 435–46.doi:10.1534/genetics.108.098145. PMC 2644938. PMID 19033152.

18. Jump up ̂  Lee T, et. al (October 2002). "Transcriptional Regulatory Networks in Saccharomyces cerevisiae". Science 298 (5594): 799–804. Bibcode:2002Sci...298..799L.doi:10.1126/science.1075090. PMID 12399584.

19. Jump up ̂  Simon I, et. al (September 2001). "Serial Regulation of Transcriptional Regulators in the Yeast Cell Cycle". Cell 106 (6): 697–708. doi:10.1016/S0092-8674(01)00494-9.PMID 11572776.

20. Jump up ̂  Sidorova JM, Mikesell GE, Breeden LL (December 1995). "Cell cycle-regulated phosphorylation of Swi6 controls its nuclear localization". Mol Biol Cell. 6 (12): 1641–1658. doi:10.1091/mbc.6.12.1641. PMC 301322. PMID 8590795.

21. Jump up ̂  Ubersax J, et. al (October 2003). "Targets of the cyclin-dependent kinase Cdk1". Nature425 (6960): 859–864. Bibcode:2003Natur.425..859U. doi:10.1038/nature02062.PMID 14574415.

22. Jump up ̂  Morgan DO (2007). "2–3". The Cell Cycle: Principles of Control. London: New Science Press. p. 18. ISBN 0-9539181-2-2.

23. Jump up ̂  L. Omberg, J. R. Meyerson, K. Kobayashi, L. S. Drury, J. F. X. Diffley and O. Alter (October 2009). "Global Effects of DNA Replication and DNA Replication Origin Activity on Eukaryotic Gene Expression". Molecular Systems Biology 5: 312.doi:10.1038/msb.2009.70. PMC 2779084. PMID 19888207.

24. Jump up ̂  O. Alter, G. H. Golub, P. O. Brown and D. Botstein, (2004). M. P. Deutscher, S. Black, P. E. Boehmer, G. D'Urso, T. Fletcher, F. Huijing, A. Marshall, B. Pulverer, B. Renault, J. D. Rosenblatt, J. M. Slingerland and W. J. Whelan, ed. (PDF). Miami Nature Biotechnology Winter Symposium: Cell Cycle, Chromosomes and Cancer. Miami Beach, FL: University of Miami School of Medicine, vol. 15 (January 31 – February 4, 2004)http://www.med.miami.edu/mnbws/documents/Alter-.pdf. Missing or empty |title=(help); |chapter= ignored (help)

25. Jump up ̂  O. Alter and G. H. Golub (November 2004). "Integrative Analysis of Genome-Scale Data by Using Pseudoinverse Projection Predicts Novel Correlation Between DNA Replication and RNA Transcription". PNAS 101 (47): 16577–16582.Bibcode:2004PNAS..10116577A. doi:10.1073/pnas.0406767101. PMC 534520.PMID 15545604.

26. Jump up ̂  L. Omberg, G. H. Golub and O. Alter (November 2007). "A Tensor Higher-Order Singular Value Decomposition for Integrative Analysis of DNA Microarray Data From Different Studies". PNAS 104 (47): 18371–18376. Bibcode:2007PNAS..10418371O.doi:10.1073/pnas.0709146104. PMC 2147680. PMID 18003902.

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28. Jump up ̂  S. Champeris Tsaniras, N. Kanellakis, I.E. Symeonidou, P. Nikolopoulou, Z. Lygerou and S. Taraviras (2014). "Licensing of DNA replication, cancer, pluripotency and differentiation: An interlinked world?". Seminars in Cell & Developmental Biology 30: 174–180.doi:10.1016/j.semcdb.2014.03.013. PMID 24641889.

CyclinFrom Wikipedia, the free encyclopedia

Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes.[1]

Contents  [hide] 

1   Function 2   Domain structure 3   Types

o 3.1   Main groups o 3.2   Subtypes o 3.3   Other proteins containing this domain

4   History 5   References 6   External links 7   Further reading

Function[edit]

Expression of human cyclins through the cell cycle.

Cyclins were originally named because their concentration varies in a cyclical fashion during the cell cycle. (Note that the cyclins are now classified according to their conserved cyclin box structure, and not all these cyclins alter in level through the cell cycle.[2]) The oscillations of the cyclins, namely fluctuations in cyclin gene expression and destruction by the ubiquitin mediated proteasome pathway, induce oscillations in Cdk activity to drive the cell cycle. A cyclin forms a complex with Cdk, which begins to activate the Cdk, but the complete activation requires phosphorylation, as well. Complex formation results in activation of the Cdk active site. Cyclins themselves have no enzymatic activity but have binding sites for some substrates and target the Cdks to specific subcellular locations.[3]

They were discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins.[4][5]

In an interview for The Life Scientific" (aired on 13/12/2011) hosted by Jim Al-Khalili, R. Timothy Huntexplained that the name "cyclin" was originally named after his hobby cycling. It was only after the naming did its importance in the cell cycle become apparent. As it was appropriate the name stuck.[6] R. Timothy Hunt: "By the way, the name cyclin, which I coined, was really a joke, it's because I liked cycling so much at the time, but they did come and go in the cell..." [7]

Cyclins, when bound with the dependent kinases, such as the p34 (cdc2) or cdk1 proteins, form the maturation-promoting factor. MPFs activate other proteins throughphosphorylation. These phosphorylated proteins, in turn, are responsible for specific events during cycle division such as microtubule formation and chromatin remodeling. Cyclins can be divided into four classes based on their behavior in the cell cycle of vertebrate somatic cells and yeast cells: G1/S cyclins, S cyclins, G2 cyclins, M cyclins. This division is useful when talking about most cell cycles, but it is not universal as some cyclins have different functions or timing in different cell types.

G1/S Cyclins rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, primarily by arresting systems that prevent S phase Cdk activity in G1. The cyclins also promote other activities to progress the cell cycle, like centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins.

S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, but through G2 and early mitosis as well to promote early events in mitosis.

M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. Cell changes in the cell cycle like the assembly of mitotic spindles and alignment of sister-chromatids along the spindles are induced by M cyclin- Cdk complexes. The destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis.[8]

G1 cyclins do not behave like the other cyclins, in that the concentrations increase gradually (with no oscillation), throughout the cell cycle based on cell growth and the external growth-regulatory signals. The presence of G cyclins coordinate cell growth with the entry to a new cell cycle.

Domain structure[edit]

Cyclins are generally very different from each other in primary structure, or amino acid sequence. However, all members of the cyclin family are similar in 100 amino acids that make up the cyclin box. Cyclins contain two domains of similar all-α fold, the first located at the N-terminus and the second at the C-terminus. All cyclins are believed to contain a similar tertiary structure of two compact domains of 5 α helices. The first of which is the conserved cyclin box, outside of which

cyclins are divergent. For example, the amino-terminal regions of S and M cyclins contain short destruction-box motifs that target these proteins for proteolysis in mitosis.

Cyclin, N-terminal domain

Structure of bovine cyclin A.[9]

Identifiers

Symbol Cyclin_N

Pfam PF00134

Pfam clan CL0065

InterPro IPR006671

PROSITE PDOC00264

SCOP 1vin

SUPERFAMILY 1vin

[show]Available protein structures:

Cyclin, C-terminal domain

Structure of CDK2-cyclin A/indirubin-5-sulphonate.[10]

Identifiers

Symbol Cyclin_C

Pfam K cyclin, C terminal

structure of a p18(ink4c)-cdk6-k-cyclin ternary complex

Identifiers

Symbol K-cyclin_vir_C

Pfam PF09080

InterPro IPR015164

SCOP 1g3n

SUPERFAMILY 1g3n

[show]Available protein structures:

PF02984

Pfam clan CL0065

InterPro IPR004367

PROSITE PDOC00264

SCOP 1vin

SUPERFA

MILY

1vin

[show]Available protein structures:

Types[edit]

There are several different cyclins that are active in different parts of the cell cycle and that cause the Cdk to phosphorylate different substrates. There are also several "orphan" cyclins for which no Cdk partner has been identified. For example, cyclin F is an orphan cyclin that is essential for G2/M transition.[11][12] A study in C. elegans revealed the specific roles of mitotic cyclins.[13]

[14] Notably, recent studies have shown that cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation. Cells must separate their chromosomes precisely, an event that relies on the bi-oriented attachment of chromosomes to spindle microtubules through specialized structures called kinetochores. In the early phases of division, there are numerous errors in how kinetochores bind to spindle microtubules. The unstable attachments promote the correction of errors by causing a constant detachment, realignment and reattachment of microtubules from kinetochores in the cells as they try to find the correct attachment. Protein cyclin A governs this process by keeping the process going until the errors are eliminated. In normal cells, persistent cyclin A expression prevents the stabilization of microtubules bound to kinetochores even in cells with aligned chromosomes. As levels of cyclin A decline, microtubule attachments become stable, allowing the chromosomes to be divided correctly as cell division proceeds. In contrast, in cyclin A-deficient cells, microtubule attachments are prematurely stabilized. Consequently, these cells may fail to correct errors, leading to higher rates of chromosome mis-segregation.[15]

Main groups[edit]There are two main groups of cyclins:

G1/S cyclins – essential for the control of the cell cycle at the G1/S transition, Cyclin A  / CDK2 – active in S phase. Cyclin D  / CDK4, Cyclin D / CDK6, and Cyclin E / CDK2 – regulates transition from G1 to

S phase.

G2/M cyclins – essential for the control of the cell cycle at the G2/M transition (mitosis). G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). Cyclin B  / CDK1 – regulates progression from G2 to M phase.

Subtypes[edit]Specific cyclin subtypes include:

Species G1 G1/S S M

S. cerevisiae Cln3 (Cdk1) Cln 1,2 (Cdk1) Clb 5,6 (Cdk1)Clb 1,2,3,4 (Cdk 1)

S. pombe Puc1? (Cdk1)Puc1, Cig1? (Cdk1)

Cig2, Cig1? (Cdk1) Cdc13 (Cdk1)

D. melanogaster

cyclin D (Cdk4) cyclin E (Cdk2)cyclin E, A (Cdk2,1)

cyclin A, B, B3 (Cdk1)

X. laeviseither not known or not present

cyclin E (Cdk2)cyclin E, A (Cdk2,1)

cyclin A, B, B3 (Cdk1)

H. sapienscyclin D 1,2,3 (Cdk4, Cdk6)

cyclin E (Cdk2)cyclin A (Cdk2, Cdk1)

cyclin B (Cdk1)

family members

A CCNA1, CCNA2

B CCNB1, CCNB2, CCNB3

C CCNC

D CCND1, CCND2, CCND3

E CCNE1, CCNE2

F CCNF

G CCNG1, CCNG2

H CCNH

I CCNI, CCNI2

J CCNJ, CCNJL

K CCNK

L CCNL1, CCNL2

O CCNO

T CCNT1, CCNT2

YCCNY, CCNYL1, CCNYL2, CCNYL3

Other proteins containing this domain[edit]In addition, the following human proteins contain a cyclin domain:

CABLES2, CNTD1, CNTD2

History[edit]

Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of cyclin and cyclin-dependent kinase.[16]

References[edit]

1. Jump up ̂  Galderisi U, Jori FP, Giordano A (August 2003). "Cell cycle regulation and neural differentiation". Oncogene 22 (33): 5208–19. doi:10.1038/sj.onc.1206558.PMID 12910258.

2. Jump up ̂  Morgan, DO (2007) 'The Cell Cycle: Principles of Control, Oxford University Press

3. Jump up ̂  (Morgan, D.O. (2007) The Cell Cycle: Principles of Control. Oxford University Press.

4. Jump up ̂  Evans et al., 1983, Cell 33, p389-3965. Jump up ̂  http://nobelprize.org/nobel_prizes/medicine/laureates/2001/hunt-autobio.html6. Jump up ̂  "The Life Scientific". BBC Radio 4. BBC. Retrieved 13 December 2011.7. Jump up ̂  "The Life Scientific". BBC Radio 4. Retrieved 13 December 2012.8. Jump up ̂  Clute and Pines, (1999) Nature Cell Biology, 1, p82-879. Jump up ̂  Brown NR, Noble ME, Endicott JA; et al. (November 1995). "The crystal

structure of cyclin A". Structure 3 (11): 1235–47. doi:10.1016/S0969-2126(01)00259-3.PMID 8591034.

10. Jump up ̂  Davies TG, Tunnah P, Meijer L; et al. (May 2001). "Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate". Structure 9(5): 389–97. doi:10.1016/S0969-2126(01)00598-6. PMID 11377199.

11. Jump up ̂  Fung TK, Poon RY (2005). "A roller coaster ride with the mitotic cyclins". Semin. Cell Dev. Biol. 16 (3): 335–42. doi:10.1016/j.semcdb.2005.02.014. PMID 15840442.

12. Jump up ̂  Gerald Karp, (2007). Cell and Molecular Biology: Concepts and Experiments. New York: Wiley. pp. 148, 165–170, and 624–664. ISBN 0-470-04217-6.

13. Jump up ̂  van der Voet, Monique; Lorson, Monique; Srinivasan, Dayalan G.; Bennett, Karen L.; van den Heuvel, Sander (2009). "C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation". Cell Cycle 8 (24): 4091–4102.doi:10.4161/cc.8.24.10171. ISSN 1538-4101.

14. Jump up ̂  Rahman, Mohammad M.; Kipreos, Edward (2010). "The specific roles of mitotic cyclins revealed". Cell Cycle 9 (1): 22–27. doi:10.4161/cc.9.1.10577. ISSN 1538-4101.

15. Jump up ̂  Nature Reviews Molecular Cell Biology (2013) doi:10.1038/nrm368016. Jump up ̂  "The Nobel Prize in Physiology or Medicine 2001". The Nobel Foundation.

Retrieved2009-03-15.

Cyclin-dependent kinaseFrom Wikipedia, the free encyclopedia

Schematic of the cell cycle. outer ring: I=Interphase, M=Mitosis; inner ring: M=Mitosis; G1=Gap phase 1;

S=Synthesis; G2=Gap phase 2. The duration of mitosis in relation to the other phases has been

exaggerated in this diagram

Cyclin-dependent kinases (CDKs) are a family of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells.[1]They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the homologous human gene. [1]

[2] CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain.[1] By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases.[1] The consensus sequence for the phosphorylationsite in the amino acid sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the phosphorylated serine orthreonine, P is proline, X is any amino acid, K is lysine, and R is arginine.[1]

Contents  [hide] 

1   Types 2   CDKs and Cyclins in the Cell Cycle 3   Regulation of CDK activity

o 3.1   Cyclin binding o 3.2   Phosphorylation o 3.3   CDK Inhibitors o 3.4   Suk1 or Cks o 3.5   Non-cyclin CDK Activators

3.5.1   Viral Cyclins 3.5.2   CDK5 Activators 3.5.3   RINGO/Speedy

4   History 5   Medical significance 6   References 7   External links

Types[edit]

Table 1: Known CDKs, their cyclin partners, and their functions in the human [3] and consequences of deletion in mice.[4]

CDKCyclin

partnerFunction Deletion Phenotype in Mice

Cdk1 Cyclin B M phase None. ~E2.5.

Cdk2 Cyclin E G1/S transitionReduced size, imparted neural progenitor cell proliferation. Viable, but both males & females sterile.

Cdk2 Cyclin A S phase, G2 phase

Cdk3 Cyclin C G1 phase ? No defects. Viable, fertile.

Cdk4 Cyclin D G1 phaseReduced size, insulin deficient diabetes. Viable, but both male & female infertile.

Cdk5 p35 TranscriptionSevere neurological defects. Died immediately after birth.

Cdk6 Cyclin D G1 phase

Cdk7 Cyclin HCDK-activating kinase, transcription

Cdk8 Cyclin C Transcription Embryonic lethal

Cdk9 Cyclin T Transcription Embryonic lethal

Cdk11

Cyclin L ? Mitotic defects. E3.5.

? Cyclin F ? Defects in extraembryonic tissues. E10.5.

? Cyclin G ?

CDKs and Cyclins in the Cell Cycle[edit]

Most of the known cyclin-CDK complexes regulate the progression through the cell cycle. Animal cells contain at least nine CDKs, four of which, CDK1, 2, 3, and 4, are directly involved in cell cycle regulation.[1] In mammalian cells, CDK1, with its partners cyclin A2 and B1, alone can drive the cell cycle.[4] Another one, CDK7, is involved indirectly as the CDK-activating kinase. [1] Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase. [3] Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase. [1]

Table 2: Cyclins and CDKs by Cell-Cycle Phase

Phase Cyclin CDK

G0 C Cdk3

G1 D, E Cdk4, Cdk2, Cdk6

S A, E Cdk2

G2 A Cdk2, Cdk1

M B Cdk1

Table 3: Cyclin-dependent kinases that control the cell cycle in model organisms. [1]

Species Name Original name Size (amino acids) Function

Saccharomyces cerevisiae Cdk1 Cdc28 298 All cell-cycle stages

Schizosaccharomyces pombe

Cdk1 Cdc2 297 All cell-cycle stages

Drosophila melanogaster Cdk1 Cdc2 297 M

Cdk2 Cdc2c 314 G1/S, S, possibly M

Cdk4 Cdk4/6 317 G1, promotes growth

Xenopus laevis Cdk1 Cdc2 301 M

Cdk2 297 S, possibly M

Homo sapiens Cdk1 Cdc2 297 M

Cdk2 298 G1, S, possibly M

Cdk4 301 G1

Cdk6 326 G1

A list of CDKs with their regulator protein, cyclin or other.

CDK1 ; cyclin A, cyclin B CDK2 ; cyclin A, cyclin E CDK3 ; cyclin C CDK4 ; cyclin D1, cyclin D2, cyclin D3 CDK5 ; CDK5R1, CDK5R2. See also CDKL5. CDK6 ; cyclin D1, cyclin D2, cyclin D3 CDK7 ; cyclin H CDK8 ; cyclin C CDK9 ; cyclin T1, cyclin T2a, cyclin T2b, cyclin K CDK10 CDK11 (CDC2L2) ; cyclin L CDK12 (CRKRS) ; cyclin L CDK13 (CDC2L5) ; cyclin L

Regulation of CDK activity[edit]

CDK levels remain relatively constant throughout the cell cycle and most regulation is post-translational. Most knowledge of CDK structure and function is based on CDKs of S. pombe (Cdc2), S. cerevisiae (CDC28), and vertebrates (CDC2 and CDK2). The four major mechanisms of CDK regulation are cyclin binding, CAK phosphorylation, regulatory inhibitory phosphorylation, and binding of CDK inhibitory subunits (CKIs).[5]

Cyclin binding[edit]The active site, or ATP-binding site, of all kinases is a cleft between a small amino-terminal lobe and a larger carboxy-terminal lobe.[1] The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding.[1] Phosphorylation by CDK-activating kinase (CAK) at Thr 161 on the T-loop increases the complex activity. Without cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, and the position of several key amino acid residues is not optimal for ATP-binding.[1] With cyclin, two alpha helices change position to permit ATP binding. One of them, the L12 helix that comes just before the T-loop in the primary sequence, becomes a beta strand and helps rearrange the T-loop, so it no longer

blocks the active site.[1] The other alpha helix called the PSTAIRE helix rearranges and helps change the position of the key amino acid residues in the active site.[1]

There is considerable specificity in which cyclin binds with CDK.[3] Furthermore, cyclin binding determines the specificity of the cyclin-CDK complex for particular substrates. [3]Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. Substrate specificity of S cyclins is imparted by the hydrophobic batch (centered on the MRAIL sequence), which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif. Cyclin B1 and B2 can localize Cdk1 to the nucleus and the Golgi, respectively, through a localization sequence outside the CDK-binding region.[1]

Phosphorylation[edit]Full kinase activity requires an activating phosphorylation on a threonine adjacent to the active site.[1] The identity of the CDK-activating kinase (CAK) that performs this phosphorylation varies across the model organisms.[1] The timing of this phosphorylation varies as well. In mammalian cells, the activating phosphorylation occurs after cyclin binding.[1] In yeast cells, it occurs before cyclin binding.[1] CAK activity is not regulated by known cell-cycle pathways and cyclin binding is the limiting step for CDK activation.[1]

Unlike activating phosphorylation, CDK inhibitory phosphorylation is vital for regulation of the cell cycle. Various kinases and phosphatases regulate their phosphorylation state. One of the kinases that place the tyrosine phosphate is Wee1, a kinase conserved in all eukaryotes.[1] Fission yeast also contains a second kinase Mik1 that can phosphorylate the tyrosine.[1] Vertebrates contain a different second kinase called Myt1 that is related to Wee1 but can phosphorylate both the threonine and the tyrosine.[1] Phosphatases from the Cdc25 family dephosphorylate both the threonine and the tyrosine.[1]

CDK Inhibitors[edit]A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA.[1] In animal cells, there are two major CKI families: the INK4 family and the CIP/KIP family.[1] The INK4 family proteins are strictly inhibitory and bind CDK monomers. Crystal structures of CDK6-INK4 complexes show that INK4 binding twists the CDK to distort cyclin binding and kinase activity. The CIP/KIP family proteins bind both the cyclin and the CDK of a complex and can be inhibitory or activating. CIP/KIP family proteins activate cyclin D and CDK4 or CDK6 complexes by enhancing complex formation.[1]

In yeast and Drosophila, CKIs are strong inhibitors of S- and M-CDK, but do not inhibit G1/S-CDKs. During G1, high levels of CKIs prevent cell cycle events from occurring out of order, but do not prevent transition through the Start checkpoint, which is initiated through G1/S-CDKs. Once the cell cycle is initiated, phosphorylation by early G1/S-CDKs leads to destruction of CKIs, relieving inhibition on later cell cycle transitions. In mammalian cells, the CKI regulation works differently. Mammalian protein p27 (Dacapo in Drosophila) inhibits G1/S- and S-CDKs, but does not inhibit S- and M-CDKs.[1]

Suk1 or Cks[edit]The CDKs directly involved in the regulation of the cell cycle associate with small, 9- to 13-kiloDalton proteins called Suk1 or Cks.[3] These proteins are required for CDK function, but their precise role is unknown.[3] Cks1 binds the carboxy lobe of the CDK, and recognizes phosphorylated residues. It may help the cyclin-CDK complex with substrates that have multiple phosphorylation sites by increasing affinity for the substrate.[3]

Non-cyclin CDK Activators[edit]Viral Cyclins[edit]

Viruses can encode proteins with sequence homology to cyclins. One much-studied example is K-cyclin (or v-cyclin) from Kaposi sarcoma herpes virus (see Kaposi’s sarcoma), which activates

CDK6. Viral cyclin-CDK complexes have different substrate specificities and regulation sensitivities.[6]

CDK5 Activators[edit]

The proteins p35 and p39 activate CDK5. Although they lack cyclin sequence homology, crystal structures show that p35 folds in a similar way as the cyclins. However, activation of CDK5 does not require activation loop phosphorylation.[6]

RINGO/Speedy[edit]

Proteins with no homology to the cyclin family can be direct activators of CDKs.[7] One family of such activators is the RINGO/Speedy family,[7] which was originally discovered in Xenopus. All five members discovered so far directly activate Cdk1 and Cdk2, but the RINGO/Speedy-CDK2 complex recognizes different substrates than cyclin A-CDK2 complex.[6]

History[edit]

Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse received the 2001 Nobel Prize in Physiology or Medicine for their complete description of cyclin and cyclin-dependent kinase mechanisms, which are central to the regulation of the cell cycle.

Medical significance[edit]

CDKs are considered a potential target for anti-cancer medication. If it is possible to selectively interrupt the cell cycle regulation in cancer cells by interfering with CDK action, the cell will die. At present, some CDK inhibitors such as seliciclib are undergoing clinical trials. Although it was originally developed as a potential anti-cancer drug, seliciclib has also proven to induce apoptosis in neutrophil granulocytes, which mediate inflammation.[8] This means that novel drugs for treatment of chronic inflammation diseases such as arthritisand cystic fibrosis could be developed.

Flavopiridol (alvocidib) is the first CDK inhibitor to be tested in clinical trials after being identified in an anti-cancer agent screen in 1992. It competes for the ATP site of the CDKs.[9]

More research is required, however, because disruption of the CDK-mediated pathway has potentially serious consequences; while CDK inhibitors seem promising, it has to be determined how side-effects can be limited so that only target cells are affected. As such diseases are currently treated with glucocorticoids, which have often serious side-effects, even a minor success would be an improvement.

Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle, but other processes such as transcription, neural physiology, and glucose homeostasis.[10]

Table 4: Cyclin-dependent kinase inhibitor drugs [10]

Drug CDKs Inhibited

Flavopiridol (alvocidib) 1, 2, 4, 6, 7, 9

Olomoucine 1, 2, 5

Roscovitine 1, 2, 5

Purvalanol 1, 2, 5

Paullones 1, 2, 5

Butryolactone 1, 2, 5

Palbociclib 4, 6

Thio/oxoflavopiridols 1

Oxindoles 2

Aminothiazoles 4

Benzocarbazoles 4

Pyrimidines 4

Seliciclib ?

References[edit]

1. ^ Jump up to: a  b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Morgan, David O. (2007). The Cell Cycle: Principles of Control. London: New Science Press, 1st ed.

2. Jump up ̂  Lee, Melanie; Nurse, Paul. (1987). "Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2." Nature 327:31-35.

3. ^ Jump up to: a  b c d e f g Morgan, David O. (1997) "Cyclin-Dependent Kinase: Engines, Clocks, and Microprocessors." Annual Review of Cell and Developmental Biology. 13:261-291.

4. ^ Jump up to: a  b Satyanarayana, A; Kaldis. (2009). “Mammalian cell-cycle regulation: several Cdks, numerous cyclins, and diverse compensatory mechanisms” “Oncogene” 28:2925-2939

5. Jump up ̂  Morgan, David O. (1995). “Principles of CDK regulation.” “Nature” 374:131-133.6. ^ Jump up to: a  b c Nebreda, Angel R. (2006) “CDK activation by non-cyclin proteins.” “Current

Opinion in Cell Biology.” 18:192-1987. ^ Jump up to: a  b Mouron, Silvana; de Carcer, Guillermo; Seco, Esther; Fernandez-Miranda,

Gonzalo; Malumbres, Marcos; Nebreda, Angel. (2010). "RINGO C is required to sustain the spindle assembly checkpoint." Journal of Cell Science. 123:2586-2595.

8. Jump up ̂  Rossi, Adriano G.; Sawatzky, Deborah A.; Walker, Annemieke; Ward, Carol; Sheldrake, Tara A.; Riley, Nicola A.; Caldicott, Alison; Martinez-Losa, Magdalena; Walker, Trevor R.; Duffin, Roger; Gray, Mohini; Crescenzi, Elvira; Martin, Morag C.; Brady, Hugh J; Savill, John S.; Dransfield, Ian & Haslett, Christopher (2006): Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine 12 (in print). doi:10.1038/nm1468

9. Jump up ̂  Senderowicz, AM. “Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials” “Invest New Drugs” 17(3):313-20

10. ^ Jump up to: a  b Sausville, Edward A. (2002) “Complexities in the development of cyclin-dependent kinase inhibitor drugs” “Trends in Molecular Medicine” 8:S32-S37

Cyclin-dependent kinase inhibitor proteinFrom Wikipedia, the free encyclopedia

Cyclin-dependent kinase inhibitor

Structure of the p27Kip1 cyclin-dependent-kinase inhibitor

bound to the cyclin A-Cdk2 complex.[1]

Identifiers

Symbol CDI

Pfam PF02234

InterPro IPR003175

SCOP 1jsu

SUPERFAMILY 1jsu

[show]Available protein structures:

This article is about the cell cycle protein. For the medical therapy, see CDK inhibitor.

A cyclin-dependent kinase inhibitor protein is a protein which inhibits cyclin-dependent kinase. Several function as tumor suppressor genes. Cell cycle progression is negatively controlled by cyclin-dependent kinases inhibitors (called CDIs, CKIs or CDKIs). CDIs are involved in cell cycle arrest at the G1  phase .

Examples[edit]

Protein Gene Interacts with

p16 CDKN2A Cyclin-dependent kinase 4, Cyclin-dependent kinase 6

p15 CDKN2B Cyclin-dependent kinase 4

Protein Gene Interacts with

p18 CDKN2C Cyclin-dependent kinase 4, Cyclin-dependent kinase 6

p19 CDKN2D Cyclin-dependent kinase 4, Cyclin-dependent kinase 6

p21 / WAF1

CDKN1A [2] Cyclin E1/Cyclin-dependent kinase 2

p27 CDKN1BCyclin D3/Cyclin-dependent kinase 4, Cyclin E1/Cyclin-dependent kinase 2

p57 CDKN1C Cyclin E1/Cyclin-dependent kinase 2

CDKN3 Cyclin-dependent kinase 2

References[edit]

1. Jump up ̂  Russo AA, Jeffrey PD, Patten AK, Massagué J, Pavletich NP (July 1996). "Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex". Nature 382(6589): 325–31. doi:10.1038/382325a0. PMID 8684460.

2. Jump up ̂  Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M (January 1999). "Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors". Oncogene 18 (3): 813–22. doi:10.1038/sj.onc.1202367. PMID 9989833.

p21From Wikipedia, the free encyclopedia

This article is about the p21Cip1 protein. For the p21/ras protein, see Ras (protein). For other uses, see P21 (disambiguation).

Cyclin-dependent kinase inhibitor 1A (p21, Cip1)

Structure of the C-terminal region of p21(WAF1/CIP1)

complexed with human PCNA.

Available structures

PDB Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

Symbols CDKN1A ; CAP20; CDKN1; CIP1; MDA-6; P21; SDI1;

WAF1; p21CIP1

External

IDs

OMIM: 116899 MGI: 104556 HomoloGene: 33

3 ChEMBL : 5021 GeneCards: CDKN1A Gene

[show]Gene ontology

RNA expression pattern

More reference expression data

Orthologs

Species Human Mouse

Entrez 1026 12575

Ensembl ENSG00000124762 ENSMUSG00000023067

UniProt P38936 P39689

RefSeq

(mRNA)

NM_000389 NM_001111099

RefSeq

(protein)

NP_000380 NP_001104569

Location

(UCSC)

Chr 6:

36.68 – 36.69 Mb

Chr 17:

29.09 – 29.1 Mb

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p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is acyclin-dependent kinase inhibitor that inhibits the complexes of CDK2 and CDK1. This protein is encoded by the CDKN1Agene located on chromosome 6 (6p21.2) in humans.[1][2][3][4]

Contents  [hide] 

1   Function 2   Clinical significance 3   Interactions 4   References 5   Further reading 6   External links

Function[edit]

p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity ofcyclin-CDK2, -CDK1, and -CDK4 /6  complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase.[5] In addition to growth arrest, p21 can mediate cellular senescence. One of the ways it was discovered was as a senescent cell-derived inhibitor.

The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli.[6] This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation.

Studies of human embryonic stem cells (hESCs) commonly report the nonfunctional p53-p21 axis of the G1/S checkpoint pathway, and its relevance for cell cycle regulation and the DNA damage response (DDR). p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. [7]

p21 can also interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair.[8] This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution ofapoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own.[9]Two alternatively spliced variants, which encode an identical protein, have been reported.

Sometimes p21 is expressed without being induced by p53. This kind of induction plays a big role in p53 independent differentiation which is promoted by p21. Expression of p21 is mainly dependent on two factors 1) stimulus provided 2) type of the cell. Growth arrest by p21 can promote cellular differentiation. p21 therefore prevents cell proliferation.[citation needed]

Despite regulation by tumor suppressor gene p53, loss-of-function mutations in p21 (unlike p53) do not accumulate in cancer nor do they predispose to cancer incidence. Mice genetically engineered to lack p21 develop normally and are not susceptible to cancer at a higher rate than wild-type mice (unlike p53 knockout mice).[citation needed]

Mice that lack the p21 gene gain the ability to regenerate lost appendages.[10]

Clinical significance[edit]

p21 mediates the resistance of hematopoietic cells to an infection with HIV [11]  by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus. HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses.[12]

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.[13][14]

Cyclin-dependent kinase 4From Wikipedia, the free encyclopedia

Cyclin-dependent kinase 4

Rendering based on PDB 1LD2.

Available structures

PDB Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

Symbols CDK4 ; CMM3; PSK-J3

External

IDs

OMIM: 123829 MGI: 88357 HomoloGene : 55429

ChEMBL: 331 GeneCards : CDK4 Gene

EC

number

2.7.11.22

[show]Gene ontology

RNA expression pattern

More reference expression data

Orthologs

Species Human Mouse

Entrez 1019 12567

Ensembl ENSG00000135446 ENSMUSG00000006728

UniProt P11802 P30285

RefSeq

(mRNA)

NM_000075 NM_009870

RefSeq

(protein)

NP_000066 NP_034000

Location

(UCSC)

Chr 12:

57.75 – 57.76 Mb

Chr 10:

127.06 – 127.07 Mb

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Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by theCDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

Contents  [hide] 

1   Function 2   Clinical significance 3   Interactions 4   References 5   Further reading 6   External links

Function[edit]

The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16 INK4a . This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb).[1]

Clinical significance[edit]

Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported.[1]

It is regulated by Cyclin D.

Interactions[edit]

Cyclin-dependent kinase 4 has been shown to interact with:

CDC37 ,[2][3][4][5]

CDKN1B ,[6][7]

CDKN2B ,[8][9]

CDKN2C ,[2][10]

CEBPA ,[11]

CCND1 ,[12][13][6][14][7][15]

CCND3 ,[8][16][6][17]

DBNL ,[2]

MyoD ,[18][19]

P16 ,[2][20][21][12][13][15]

PCNA ,[13][22] and SERTAD1 .[21][12]

Overview of signal transduction pathways involved in apoptosis.

Cyclin-dependent kinase 6From Wikipedia, the free encyclopedia

Cyclin-dependent kinase 6

PDB rendering based on 1bi7.

Available structures

PDB Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

Symbols CDK6 ; MCPH12; PLSTIRE

External

IDs

OMIM: 603368 MGI: 1277162 HomoloGene : 963 C

hEMBL: 2508 GeneCards:CDK6 Gene

EC

number

2.7.11.22

[show]Gene ontology

RNA expression pattern

More reference expression data

Orthologs

Species Human Mouse

Entrez 1021 12571

Ensembl ENSG00000105810 ENSMUSG00000040274

UniProt Q00534 Q64261

RefSeq

(mRNA)

NM_001145306 NM_009873

RefSeq

(protein)

NP_001138778 NP_034003

Location

(UCSC)

Chr 7:

92.6 – 92.84 Mb

Chr 5:

3.34 – 3.53 Mb

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e

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene.[1][2] It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins.[3] The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4.[4] CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.[5]

This kinase is a catalytic subunit of the protein kinase complex, important for the G1 phase progression and G1/S transition of the cell cycle and the complex is composed also by an activating sub-unit; the cyclin D.[6] The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors.[3] This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor Retinoblastoma protein making CDK6 an important protein in cancer development.[6]

Contents  [hide] 

1   Structure

2   Function o 2.1   Cell cycle o 2.2   Cellular development o 2.3   DNA protection o 2.4   Metabolic homeostasis o 2.5   Centrosome stability

3   Mechanisms of regulation 4   Clinical relevance

o 4.1   Cancer o 4.2   Medulloblastoma o 4.3   As a drug target o 4.4   Interactions

5   See also 6   References 7   Further reading 8   External links

Structure[edit]

The CDK6 gene is conserved in eukaryotes, including the budding yeast and the nematode Caenorhabditis elegans.[7] The CDK6 gene is located in the chromosome 7 in humans, it is encoded by 231,706 base pairs and is translated to a 326 amino acid protein with a kinase function.[2] The gene is over expressed in cancers like lymphoma, leukemia,medulloblastoma and melanoma associated with chromosomal rearrangements.[2] The CDK6 protein contains a catalytic core composed of a serine/threonine domain.[8] This protein also contains an ATP-binding pocket, inhibitory and activating phosphorylation sites, a PSTAIRE-like cyclin-binding domain and an activating T-loop motif.[6] After binding the Cyclin in the PSTAIRE helix, the protein changes its conformational structure to expose the phosphorylation motif.[6] The protein can be found in the cytoplasm and the nucleus, however most of the active complexes are found in the nucleus of proliferating cells.[6]

Function[edit]

Cell cycle[edit]In 1994, Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4.[3] This gene, identified as PLSTIRE was translated into a protein that interacted with the cyclins CD1, CD2 and CD3 (same as CDK4), but that was different from CDK4; the protein was then renamed CDK6 for simplicity.[3] In mammalian cells, cell cycle is activated by CDK6 in the early G1 phase[9] through interactions with cyclins D1, D2 and D3.[3] There are many changes in gene expression that are regulated through this enzymes.[10] After the complex is formed, the C-CDK6 enzymatic complex phosphorylates the protein pRb.[11] After its phosphorylation, pRb releases its binding partner E2F, a transcriptional activator, which in turns activate DNA replication.[12] The CDK6 complex ensures a point of switch to commit to division responding to external signals, like mitogens and growth factors.[13]

CDK6 is involved in a positive feedback loop that activates transcription factors through a reaction cascade.[14] Importantly, these C-DCK complexes act as a kinase, phosphorylating and inactivating the protein of Rb and p-Rb related “pocket proteins” p107 and p130. [15] While doing this, the CDK6 in conjunction with CDK4, act as a switch signal that first appears in G1,[3] directing the cell towards S phase of the cell cycle.[10]

CDK6 is important for the control of G1 to S phase transition.[3] However, in recent years, new evidence proved that the presence of CDK6 is not essential for proliferation in every cell type,[16] the cell cycle has a complex circuitry of regulation and the role of CDK6 might be more

important in certain cell types than in others, where CDK4 or CDK2 can act as protein kinases compensating its role.[16][17]

Cellular development[edit]In mutant Knockout mice of CDK6, the hematopoietic function is impaired, regardless of otherwise organism normal development.[16] This might hint additional roles of CDK6 in the development of blood components.[16] There are additional functions of CDK6 not associated with its kinase activity.[18] For example, CDK6 is involved in the differentiation of T cells, acting as an inhibitor of differentiation.[18] Even though CDK6 and CDK4 share 71% amino acid identity, this role in differentiation is unique to CDK6.[18] CDK6 has also been found to be important in the development of other cell lines, for example, CDK6 has a role in the alteration of the morphology of astrocytes [19]  and in the development of other stem cells.[6][12]

DNA protection[edit]CDK6 differs from CDK4 in other important roles.[20] For example, CDK6 plays a role in the accumulation of the apoptosis proteins p53 and p130, this accumulation avoids cells from entering cell division if there is DNA damage, activating pro- apoptotic pathways.[20]

Metabolic homeostasis[edit]Studies in the metabolic control of cells have revealed yet another role of CDK6. [21] This new role is associated with the balance of the oxidative and non-oxidative branches of the pentose pathway in cells.[21] This pathway is a known route altered in cancer cells, when there is an aberrant overexpression of CDK6 and CDK4.[21] The overepression of these proteins provides the cancer cells with a new hallmark capability of cancer; the deregulation of the cell metabolism. [21]

Centrosome stability[edit]In 2013 researches discovered yet another additional role of CDK6.[22] There is evidence that CDK6 associates with the centrosome and controls organized division and cell cycle phases in neuron production.[22] When the CDK6 gene is mutated in these developing lines, the centrosomes are not properly divided, this could lead to division problems such as aneuploidy, which in turns leads to health issues like primary microcephaly.[22]

Mechanisms of regulation[edit]

CDK6 is positively regulated primarily by its union to the D cyclins D1,D2 and D3. If this subunit of the complex is not available, CDK6 is not active or available to phosphorylate the pRb substrate.[5] An additional positive activator needed by CDK6 is the phosphorylation in a conserved threonine residue located in 177 position, this phosphorylation is done by the cdk-activating kinases, CAK.[23] Additionally, CDK6 can be phosphorylated and activated by the Kaposi's sarcoma-associated herpes virus, stimulating the CDK6 over activation and uncontrolled cell proliferation.[24]

CDK6 is negatively regulated by binding to certain inhibitors that can be classified in two groups;[25] CKIs or CIP/KIP family members like the protein p21[12] and p27 act blocking and inhibiting the assembled C-CDKs binding complex enzymes[23] in their catalytic domain.[26]

Furthermore, inhibitors of the INK4 family members like p15, p16, p18 and p19 inhibit the monomer of CDK6, preventing the complex formation.[15][27]

Clinical relevance[edit]

CDK6 is a protein kinase activating cell proliferation, it is involved in an important point of restriction in the cell cycle.[14] For this reason, CDK6 and other regulators of the G1 phase of the cell cycle are known to be unbalanced in more than 80-90% of tumors.[5] In cervical cancer cells, CDK6 function has been shown to be altered indirectly by the p16 inhibitor.[27] CDK6 is also overexpressed in tumors that exhibit drug resistance, for example glioma malignancies exhibit resistance to chemotherapy using Temozolomide (TMZ) when they have a mutation

overexpressing CDK6.[28] Likewise, the overexpression of CDK6 is also associated with resistance to hormone therapy using the anti oestrogen Fluvestrant in breast cancer.[29]

Cancer[edit]Loss of normal cell cycle control is the first step to developing different hallmarks of cancer; alterations of CDK6 can directly or indirectly affect the following hallmarks; disregulated cell cellular energetics, sustaining of proliferative signaling, evading growth suppressors and inducing angiogenesis,[5] for example, deregulation of CDK6 has been shown to be important in lymphoid malignancies by increasing angiogenesis, a hallmark of cancer.[15] These features are reached through upregulation of CDK6 due to chromosome alterations or epigenetic dysregulations.[5] Additionally, CDK6 might be altered through genomic instability, a mechanism of downregulation of tumor suppressor genes; this represents another evolving hallmark of cancer.[30]

Medulloblastoma[edit]Medulloblastoma is the most common cause of brain cancer in children.[31] About a third of these cancers have upregulated CDK6, representing a marker for poor prognosis for this disease.[31] Since it is so common for these cells to have alterations in CDK6, researchers are seeking for ways to downregulate CDK6 expression acting specifically in those cell lines. The MicroRNA (miR) -124 has successfully controlled cancer progression in an in-vitro setting for medulloblastoma and glioblastoma cells.[31] Furthermore, researchers have found that it successfully reduces the growth of xenograft tumors in rat models.[31]

As a drug target[edit]The direct targeting of CDK6 and CDK4 should be used with caution in the treatment of cancer, the reason why is because these enzymes are important for the cell cycle of normal cells we well.[31] Furthermore, small molecules targeting these proteins might increase drug resistance events.[31] However, these kinases have been shown to be useful as coadjuvants in breast cancer chemotherapy.[32] Another indirect mechanism for the control of CDK6 expression, is the use of a mutated D-cyclin that binds with high affinity to CDK6, but does not induce its kinase activity.[32] this mechanism was studied in the development of mammary tumorigenesis in rat cells, however, the clinical effects have not yet been shown in human patients.[32] As of 2014, different drugs to target these type of kinases have been developed, however none of those have been yet approved for the treatment of human cancers by the FDA.[33] Inhibitors of CDK6 have shown the disadvantage of not being specific in the union to the CDK6, and as a consequence they might act inhibiting other CDKs that are crucial in other tissues and at other points of cell cycle.[33] The compound PD-0332991, is currently under more than 20 clinical trials acting either as single agent or as coadjuvant of other therapies in clinical trial phase I-III showing promising results in the control of breast cancer in-vitro.[34]

Interactions[edit]Cyclin-dependent kinase 6 interacts with:

CDKN2C ,[35][36][37]

Cyclin D1 ,[38][39]

Cyclin D3 ,[38][40]

P16 ,[41][42][43]

PPM1B ,[44] and PPP2CA .[44]

Cyclin AFrom Wikipedia, the free encyclopedia

cyclin A1

Identifiers

Symbol CCNA1

Entrez 8900

HUGO 1577

OMIM 604036

RefSeq NM_003914

UniProt P78396

Other data

Locus Chr. 13 q12.3-q13

cyclin A2

Identifiers

Symbol CCNA2

Alt. symbols CCNA, CCN1

Entrez 890

HUGO 1578

OMIM 123835

RefSeq NM_001237

UniProt P20248

Other data

Locus Chr. 4 q27

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle.[1] The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle[2] Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such

regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.[1][3]

Contents  [hide] 

1   Types 2   Role in Cell Cycle Progression

o 2.1   CDK Partner Association o 2.2   S Phase o 2.3   G 2  / M Phase

3   Regulation o 3.1   E2F and pRb o 3.2   p53 and p21

4   References 5   External links

Types[edit]

Cyclin A was first identified in 1983 in sea urchin embryos.[4] Since its initial discovery, homologues of cyclin A have been identified in numerous eukaryotes including Drosophila,[5] Xenopus, mice, and in humans but has not been found in lower eukaryotes like yeast.[6][7] The protein exists in both an embryonic form and somatic form. A single cyclin A gene has been identified in Drosophila while Xenopus, mice and humans contain two distinct types of cyclin A: A1, the embryonic-specific form, and A2, the somatic form. Cyclin A1 is prevalently expressed during meiosis and early on in embryogenesis. Cyclin A2 is expressed in dividing somatic cells.[7]

Role in Cell Cycle Progression[edit]

Cyclin A, along with the other members of the cyclin family, regulates cell cycle progression through physically interacting with cyclin-dependent kinases (CDKs),[8][9] which thereby activates the enzymatic activity of its CDK partner.[1][2][8]

CDK Partner Association[edit]The interaction between the cyclin box, a region conserved across cyclins, and a region of the CDK, called thePSTAIRE, confers the foundation of the cyclin-CDK complex.[10] Cyclin A is the only cyclin that regulates multiple steps of the cell cycle.[7] Cyclin A can regulate multiple cell cycle steps because it associates with, and thereby activates, two distinct CDKs- CDK2 and CDK1.[1] Depending on which CDK partner cyclin A binds, the cell will continue through the S phase or it will transition from G2 to the M phase.[1][3][10] Association of cyclin A with

CDK2 is required for passage into S phase while association with CDK1 is required for entry into M phase.[10]

S Phase[edit]Cyclin A resides in the nucleus during S phase where it is involved in the initiation and completion of DNA replication.[1][6][9] As the cell passes from G1 into S phase, cyclin A associates with CDK2, replacing cyclin E. Cyclin E is responsible for initiating the assembly of the pre-replication complex. This complex makes chromatin capable of replication. When the amount of cyclin A/CDK2 complex reaches a threshold level, it terminates the assembly of the pre-replication complex made by cyclin E/CDK2. As the amount of Cyclin A/CDK2 complex increases, the complex initiates DNA replication.[11]

Cyclin A has a second function in S phase, in addition to initiating DNA synthesis, Cyclin A ensures that DNA is replicated once per cell cycle by preventing the assembly of additional replication complexes.[7][11][12] This is thought to occur through the phosphorylation of particular DNA replication machinery components, such as CDC6, by the cyclin A/CDK2 complex.[1][7] Since the action of cyclin A/CDK2 inhibits that of cyclin E/CDK2, the sequential activation of cyclin E followed by the activation of cyclin A is important and tightly regulated in S phase. [7][11]

G2 / M Phase[edit]In late S phase, cyclin A can also associate with CDK1.[1][2][7] Cyclin A remains associated with CDK1 from late S into late G2 phase when it is replaced by cyclin B. Cyclin A/CDK1 is thought to be involved in the activation and stabilization of cyclin B/CDK1 complex.[7][8] Once cyclin B is activated, cyclin A is no longer needed and is subsequently degraded through the ubiquitin pathway.[3][7] Degradation of cyclin A/CDK1 induces mitotic exit.[7]

Cyclin A/CDK2 complex was thought to be restricted to the nucleus and thus exclusively involved in S phase progression. New research has since debunked this assumption, shedding light on cyclin A/CDK2 migration to the centrosomes in late G2.[1][8] Cyclin A binds to the mitotic spindle poles in the centrosome however, the mechanism by which the complex is shuttled to the centrosome is not well understood. It is suspected that the presence of cyclin A/CDK2 at the centrosomes may confer a means of regulating the movement of cyclin B/CDK1 to the centrosome and thus the timing of mitotic events.[1][6][8]

A study in 2008[8] provided further evidence of cyclin A/CDK2 complex’s role in mitosis. Cells were modified so their CDK2 was inhibited and their cyclin A2 gene was knocked out. These mutants entered mitosis late due to a delayed activation of the cyclin B/CDK1 complex. Coupling of microtubule nucleation in the centrosome with mitotic events in the nucleus was lost in the cyclin A knockout/CDK2 inhibited mutant cells.

Cyclin A has been shown to play a crucial role in the G2/M transition in Drosophila and Xenopus embryos.[3][6]

Regulation[edit]

Transcription of cyclin A is tightly regulated and synchronized with cell cycle progression.[2]

[3] Initiation of transcription of cyclin A is coordinated with passage of the R point,[2] a critical transition point that is required for progression from G1 into S phase. Transcription peaks and plateaus mid-S phase and abruptly declines in late G2.[7][12]

E2F and pRb[edit]Transcription of cyclin A is predominantly regulated by the transcription factor   E2F  in a negative feedback loop. E2F is responsible for initiating the transcription of many critical S phase genes.[1]

[3][6] Cyclin A transcription is off during most of G1 and the begins shortly after the R point.[3][7]

The retinoblastoma protein (pRb) is involved in the regulation of cyclin A through its interaction with E2F. It exists in two states: hypophosphorylated pRb and hyperphosphorylated pRb.[2] Hypophosphorylated pRb binds E2F, which prevents transcription of cyclin A. The absence of cyclin A prior to the R point is due to the inhibition of E2F by hypophosphorylated pRb. After the

cell passes through the R point, cyclin D/E- complexes phosphorylate pRb. Hyperphosphorylated pRb can no longer bind E2F, E2F is released and cyclin A genes, and other crucial genes for S phase, are transcribed.[2][9][12]

E2F initiates transcription of cyclin A by de-repressing the promoter.[7][12] The promoter is bound by a repressor molecule called the cell-cycle-responsive element (CCRE). E2F binds to an E2F binding site on the CCRE, releasing the repressor from the promoter and allowing the transcription of cyclin A.[5][7] Cyclin A/CDK2 will eventually phosphorylate E2F when cyclin A reaches a certain level, completing the negative feedback loop. Phosphorylation of E2F turns the transcription factor off, providing another level of controlling the transcription of cyclin A.[7]

p53 and p21[edit]Transcription of cyclin A is indirectly regulated by the tumor suppressor protein   p53 . P53 is activated by DNA damage and turns on several downstream pathways, including cell cycle arrest. Cell cycle arrest is carried out by the p53-pRb pathway.[13] Activated p53 turns on genes for p21. P21 is a CDK inhibitor that binds to several cyclin/CDK complexes, including cyclin A-CDK2/1 and cyclin D/CDK4, and blocks the kinase activity of CDKs.[9][13] Activated p21 can bind cyclin D/CDK4 and render it incapable of phosphorylating pRb. PRb remains hypophosphorylated and binds E2F. E2F is unable to activate the transcription of cyclins involved in cell cycle progression, such as cyclin A and the cell cycle is arrested at G1.[6][13] Cell cycle arrest allows the cell to repair DNA damage before the cell divides and passes damaged DNA to daughter cells.

References[edit]

1. ^ Jump up to: a  b c d e f g h i j k Bendris N, Lemmers B, Blanchard JM, Arsic N (2011). "Cyclin A2 mutagenesis analysis: a new insight into CDK activation and cellular localization requirements". PLoS ONE 6 (7): e22879. doi:10.1371/journal.pone.0022879.PMC 3145769. PMID 21829545.

2. ^ Jump up to: a  b c d e f g Weinberg RE (2007). The biology of cancer. New York: Garland Science.ISBN 0-8153-4076-1.

3. ^ Jump up to: a  b c d e f g Henglein B, Chenivesse X, Wang J, Eick D, Bréchot C (June 1994)."Structure and cell cycle-regulated transcription of the human cyclin A gene". Proc. Natl. Acad. Sci. U.S.A. 91 (12): 5490–4. doi:10.1073/pnas.91.12.5490. PMC 44021.PMID 8202514.

4. Jump up ̂  Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T (June 1983). "Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division". Cell 33 (2): 389–96. doi:10.1016/0092-8674(83)90420-8. PMID 6134587.

5. ^ Jump up to: a  b Huet X, Rech J, Plet A, Vié A, Blanchard JM (July 1996). "Cyclin A expression is under negative transcriptional control during the cell cycle". Mol. Cell. Biol. 16 (7): 3789–98. PMC 231375. PMID 8668196.

6. ^ Jump up to: a  b c d e f Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G (March 1992). "Cyclin A is required at two points in the human cell cycle". EMBO J. 11 (3): 961–71.PMC 556537. PMID 1312467.

7. ^ Jump up to: a  b c d e f g h i j k l m n o Yam CH, Fung TK, Poon RY (August 2002). "Cyclin A in cell cycle control and cancer". Cell. Mol. Life Sci. 59 (8): 1317–26. doi:10.1007/s00018-002-8510-y. PMID 12363035.

8. ^ Jump up to: a  b c d e f De Boer L, Oakes V, Beamish H, Giles N, Stevens F, Somodevilla-Torres M, Desouza C, Gabrielli B (July 2008). "Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events". Oncogene 27 (31): 4261–8. doi:10.1038/onc.2008.74.PMID 18372919.

9. ^ Jump up to: a  b c d Soucek T, Pusch O, Hengstschläger-Ottnad E, Adams PD, Hengstschläger M (May 1997). "Deregulated expression of E2F-1 induces cyclin A- and E-associated kinase activities independently from cell cycle position". Oncogene 14 (19): 2251–7.doi:10.1038/sj.onc.1201061. PMID 9178900.

10. ^ Jump up to: a  b c Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP (July 1995). "Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex". Nature 376 (6538): 313–20. doi:10.1038/376313a0. PMID 7630397.

11. ^ Jump up to: a  b c Coverley D, Laman H, Laskey RA (July 2002). "Distinct roles for cyclins E and A during DNA replication complex assembly and activation". Nat. Cell Biol. 4 (7): 523–8.doi:10.1038/ncb813. PMID 12080347.

12. ^ Jump up to: a  b c d Woo RA, Poon RY (2003). "Cyclin-dependent kinases and S phase control in mammalian cells". Cell Cycle 2 (4): 316–24. doi:10.4161/cc.2.4.468. PMID 12851482.

13. ^ Jump up to: a  b c Levine AJ (February 1997). "p53, the cellular gatekeeper for growth and division".Cell 88 (3): 323–31. doi:10.1016/S0092-8674(00)81871-1. PMID 9039259.

Cyclin BFrom Wikipedia, the free encyclopedia

cyclin B1

Structure of human cyclin B.[1]

Identifiers

Symbol CCNB1

Alt. symbols CCNB

Entrez 891

HUGO 1579

OMIM 123836

RefSeq NM_031966

UniProt P14635

Other data

Locus Chr. 5 q12

cyclin B2

Identifiers

Symbol CCNB2

Entrez 9133

HUGO 1580

OMIM 602755

RefSeq NM_004701

UniProt O95067

Other data

Locus Chr. 15 q21.3

cyclin B3

Identifiers

Symbol CCNB3

Entrez 85417

HUGO 18709

OMIM 300456

RefSeq NM_033670

UniProt Q8WWL7

Other data

Locus Chr. X p11

Cyclin B is a member of the cyclin family.

Cyclin B is a mitotic cyclin. The amount of cyclin B (which binds to Cdk1) and the activity of the cyclin B-Cdk complex rise through the cell cycle [2]  until mitosis, where they fall abruptly due to degradation of cyclin B (Cdk1 is constitutively present).[3] The complex of Cdk and cyclin B is called maturation promoting factor or mitosis promoting factor (MPF).

Contents  [hide] 

1   Function 2   Role in Cancer

o 2.1   As a Biomarker o 2.2   Cyclin B and p53

3   See also 4   References 5   External links

Function[edit]

Cyclin B is necessary for the progression of the cells into and out of M phase of the cell cycle.

At the end of S phase the phosphatase cdc25c dephosphorylates tyrosine15 and this activates the cyclin B/CDK1 complex. Upon activation the complex is shuttled to the nucleus where it serves to trigger for entry into mitosis.[4] However, if DNA damage is detected alternative proteins are activated which results in the inhibitory phosphorylation of cdc25c and therefore cyclinB/CDK1 is not activated. In order for the cell to progress out of mitosis, the degradation of cyclin B is necessary.[5]

The cyclin B/CDK1 complex also interacts with a variety of other key proteins and pathways which regulate cell growth and progression of mitosis. Cross-talk between many of these pathways links cyclin B levels indirectly to induction of apoptosis. The cyclin B/CDK1 complex plays a critical role in the expression of the survival signal survivin. Survivin is necessary for proper creation of the mitotic spindle which strongly affects cell viability, therefore when cyclin B levels are disrupted cells experience difficulty polarizing.[6] A decrease in survivin levels and the associated mitotic disarray triggers apoptosis via caspase 3 mediated pathway.

Role in Cancer[edit]

Cyclin B plays in integral role in many types of cancer. Hyperplasia (uncontrolled cell growth) is one of the hallmarks of cancer. Because cyclin B is necessary for cells to enter mitosis and therefore necessary for cell division, cyclin B levels are often de-regulated in tumors. When cyclin B levels are elevated, cells can enter M phase prematurely and strict control over cell division is lost, which is a favorable condition for cancer development. On the other hand, if cyclin B levels are depleted the cyclin B/CDK1 complex cannot form, cells cannot enter M phase and cell division slows down. Some anti-cancer therapies have been designed to prevent cyclin B/CDK1 complex formation in cancer cells to slow or prevent cell division. Most of these methods have targeted the CDK1 subunit, but there is an emerging interest in the oncology field to target cyclin B as well.

As a Biomarker[edit]Cyclin levels can easily be determined through immunohistological analysis of tumor biopsies. The fact that cyclin B is often disregulated in cancer cells makes cyclin B an attractive biomarker. Many studies have been performed to examine cyclin levels in tumors, and it has been shown that levels of cyclin B is a strong indicator of prognosis in many types of cancer.[7] Generally, elevated levels of cyclin B are indicative of more aggressive cancers and a poor prognosis. Immunohistologically assessed levels of cyclin B could determine if women with stage 1, node negative, hormone receptor positive breast cancer were likely to benefit from adjuvant therapy.[8] In general women with this cancer have a very good prognosis, with mortality in 10 years of only 5%. Therefore, it is rare for oncologists to recommend adjuvant chemotherapy in these cases. However, in a small subset of patient this type of cancer is unexpectedly aggressive. These rare patients can be identified through their elevated cyclin B levels. In addition high levels of cyclin B also indicate poor prognosis and lymph node metastasis in gastric cancers.[9] However, not all cancers which overexpress cyclin B are more aggressive. A study in 2009 found that cyclin B overexpression in ovarian cancer indicates that the cancer is unlikely to be malignant while more aggressive ovarian cancers of epithelial cell origin do not show elevated cyclin B.[10]

Cyclin B and p53[edit]There is strong cross-talk between the pathways regulating cyclin B and the tumor suppressor gene p53. In general levels of p53 and cyclin B are negatively correlated. When p53 build-up

triggers cell cycle arrest the levels of downstream proteins p21 and WAF1 are increased which prevents cyclinB/CDK1 complex activation and therefore progression through the cell cycle. [11] It has also been observed that decreasing cyclin B levels in cells increases the levels of functional p53.[12] Therefore, siRNAs for cyclin B may be an effective treatment against cancers where p53 function is inhibited but the gene has not been deleted. In such cases lowering cyclin B levels restores the tumor suppressing function of p53 and also prevents cancer cells from dividing as a consequence of low cyclin B.

See also[edit]

Cyclin B1 Cyclin B2

References[edit]

1. Jump up ̂  PDB: 2B9R; Petri, E.T., Errico, A., Escobedo, L., Hunt, T., and Basavappa, R. (2007). "The crystal structure of human cyclin B". Cell Cycle 11 (11): 1342–9.doi:10.4161/cc.6.11.4297. PMID 17495533.

2. Jump up ̂  Ito M (August 2000). "Factors controlling cyclin B expression" (PDF). Plant Mol. Biol.43 (5–6): 677–90. doi:10.1023/A:1006336005587. PMID 11089869.

3. Jump up ̂  Hershko A (September 1999). "Mechanisms and regulation of the degradation of cyclin B". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 354 (1389): 1571–5; discussion 1575–6.doi:10.1098/rstb.1999.0500. PMC 1692665. PMID 10582242.

4. Jump up ̂  Ford HL, Pardee AB (1999). "Cancer and the cell cycle". J. Cell. Biochem. Suppl 32-33: 166–72. doi:10.1002/(SICI)1097-4644(1999)75:32+<166::AID-JCB20>3.0.CO;2-J.PMID 10629116.

5. Jump up ̂  Zhou XY, Wang X, Hu B, Guan J, Iliakis G, Wang Y (March 2002). "An ATM-independent S-phase checkpoint response involves CHK1 pathway". Cancer Res. 62 (6): 1598–603.PMID 11912127.

6. Jump up ̂  O'Connor DS, Wall NR, Porter AC, Altieri DC (July 2002). "A p34(cdc2) survival checkpoint in cancer". Cancer Cell 2 (1): 43–54. doi:10.1016/S1535-6108(02)00084-3.PMID 12150824.

7. Jump up ̂  Agarwal R, Gonzalez-Angulo AM, Myhre S, Carey M, Lee JS, Overgaard J, Alsner J, Stemke-Hale K, Lluch A, Neve RM, Kuo WL, Sorlie T, Sahin A, Valero V, Keyomarsi K, Gray JW, Borresen-Dale AL, Mills GB, Hennessy BT (June 2009). "Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer". Clin. Cancer Res. 15 (11): 3654–62. doi:10.1158/1078-0432.CCR-08-3293.PMC 2887710. PMID 19470724.

8. Jump up ̂  Koliadi A, Nilsson C, Holmqvist M, Holmberg L, de La Torre M, Wärnberg F, Fjällskog ML (August 2010). "Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer". Acta Oncol 49 (6): 816–20. doi:10.3109/02841861003691937. PMID 20307242.

9. Jump up ̂  Begnami MD, Fregnani JH, Nonogaki S, Soares FA (August 2010). "Evaluation of cell cycle protein expression in gastric cancer: cyclin B1 expression and its prognostic implication". Hum. Pathol. 41 (8): 1120–7. doi:10.1016/j.humpath.2010.01.007.PMID 20334896.

10. Jump up ̂  Zheng H, Hu W, Deavers MT, Shen DY, Fu S, Li YF, Kavanagh JJ (October 2009). "Nuclear cyclin B1 is overexpressed in low-malignant-potential ovarian tumors but not in epithelial ovarian cancer". Am. J. Obstet. Gynecol. 201 (4): 367.e1–6.doi:10.1016/j.ajog.2009.05.021. PMID 19608149.

11. Jump up ̂  Nigam N, Prasad S, George J, Shukla Y (April 2009). "Lupeol induces p53 and cyclin-B-mediated G2/M arrest and targets apoptosis through activation of caspase in mouse skin".Biochem. Biophys. Res. Commun. 381 (2): 253–8. doi:10.1016/j.bbrc.2009.02.033.PMID 19232320.

12. Jump up ̂  Kreis NN, Sanhaji M, Krämer A, Sommer K, Rödel F, Strebhardt K, Yuan J (October 2010). "Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells". Oncogene 29 (41): 5591–603.doi:10.1038/onc.2010.290. PMID 20661218.

Cyclin DFrom Wikipedia, the free encyclopedia

cyclin D1

Crystal structure of human cyclin D1 (blue/green) in

complex with cyclin-dependent kinase 4 (yellow/red).[1]

Identifiers

Symbol CCND1

Alt. symbols BCL1, D11S287E, PRAD1

Entrez 595

HUGO 1582

OMIM 168461

RefSeq NM_053056

UniProt P24385

Other data

Locus Chr. 11 q13

cyclin D2

Identifiers

Symbol CCND2

Entrez 894

HUGO 1583

OMIM 123833

RefSeq NM_001759

UniProt P30279

Other data

Locus Chr. 12 p13

cyclin D3

Identifiers

Symbol CCND3

Entrez 896

HUGO 1585

OMIM 123834

RefSeq NM_001760

UniProt P30281

Other data

Locus Chr. 6 p21

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 (in zebra mussel) to 477 (in Drosophila) amino acids in length.[2]

Contents  [hide] 

1   Introduction 2   Homologues 3   Function

o 3.1   Cyclins in humans 4   Regulation

o 4.1   Regulation in humans o 4.2   Regulation in yeast

5   Role in cancer 6   Mutant phenotype 7   See also 8   References 9   External links

Introduction[edit]

Once the cells reach a critical cell size (and if no mating partner is present in yeast) and if growth factors and mitogens (for multicellular organism) or nutrients (for unicellular organism) are

present, cells enter the cell cycle. In general, all stages of the cell cycle are chronologically separated in humans and are triggered by cyclin-Cdk complexes which are periodically expressed and partially redundant in function. Cyclins are eukaryotic proteins that form holoenzymes with cyclin-dependent protein kinases (Cdk), which they activate. The abundance of cyclins is generally regulated by protein synthesis and degradation through an APC/Cdependent pathway.

Cyclin D is one of the major cyclins produced in terms of its functional importance. It interacts with four Cdks: Cdk2, 4, 5, and 6. In proliferating cells, cyclin D-Cdk4/6 complex accumulation is of great importance for cell cycle progression. Namely, cyclin D-Cdk4/6 complex partially phosphorylates retinoblastoma tumor suppressor protein (Rb), whose inhibition can induce expression of some genes (for example: cyclin E) important for S phase progression.

Mice, Drosophila and many other organisms only have one cyclin D protein. In humans, in addition to the mouse homologue, two more cyclin D proteins have been identified. These human proteins, called cyclin D1, cyclin D2, and cyclin D3 are expressed in most proliferating cells and the relative amounts expressed differ in various cell types.[3]

Homologues[edit]

The most studied homologues of cyclin D are found in yeast and viruses.

The yeast homologue of cyclin D, referred to as Cln3, interacts with Cdc28 (cell division control protein) during G1.

In viruses, like Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8/Kaposi's sarcoma-associated herpesvirus) cyclin D homologues have acquired new functions in order to manipulate the host cell’s metabolism to the viruses’ benefit.[4] Viral cyclin D binds human Cdk6 and inhibits Rb by phosphorylating it, resulting in free transcription factors which result in protein transcription that promotes passage through G1 phase of the cell cycle. Other than Rb, viral cyclin D-Cdk6 complex also targets p27Kip, a Cdk inhibitor of cyclin E and A. In addition, viral cyclin D-Cdk6 is resistant to Cdk inhibitors, such as p21 CIP1 /WAF1and p16 INK4a  which in human cells inhibits Cdk4 by preventing it from forming an active complex with cyclin D. [4] [5]

Function[edit]

Cyclins in humans[edit]Growth factors stimulate the Ras/Raf/ERK that induce cyclin D production. One of the members of the pathways, MAPK activates a transcription factor Myc, which alters transcription of genes important in cell cycle, among which is cyclin D. In this way, cyclin D is synthesized as long as the growth factor is present.

Even though cyclin D levels in proliferating cells are sustained as long as the growth factors are present, a key player for G1/S transition is active cyclin D-Cdk4/6 complexes. Despite this, cyclin D has no effect on G1/S transition unless it forms a complex with Cdk 4 or 6.

One of the best known substrates of cyclin D/Cdk4 and -6 is the retinoblastoma tumor suppressor protein (Rb). Rb is an important regulator of genes responsible for progression through the cell cycle, in particular through G1/S phase.

In its un-phosphorylated form, Rb binds a member of E2F family of transcription factors which controls expression of several genes involved in cell cycle progression (example, cyclin E). Rb acts as a repressor, so in complex with E2F it prevents expression of E2F-regulated genes, and this inhibits cells from progressing through G1. Active cyclin D/Cdk4 and -6 inhibit Rb by partial phosphorylation, reducing its binding to E2F and thereby allowing E2F-mediated activation of the transcription of the cyclin E gene and the cell progresses towards S-phase. Subsequently, cyclin E fully phosphorylates Rb and completes its inactivation.[6]

Regulation[edit]

Regulation in humans[edit]Cyclin D is regulated by the downstream pathway of mitogen receptors via the Ras/MAP kinase and the β-catenin-Tcf/LEF pathways and PI3K. The MAP kinase ERK activates the downstream transcription factors Myc and AP-1 which in turn activate the transcription of the Cdk4, Cdk6 and cyclin D genes, and increase ribosome biogenesis. Rho familyGTPases and focal adhesion kinase (FAK) activate cyclin D gene in response to integrin.[7]

p27kip1 and p21cip1 are cyclin-dependent kinase inhibitors (CKIs) which negatively regulate CDKs. However they are also promoters of the cyclin D-CDK4/6 complex. Without p27 and p21, cyclin D levels are reduced and the complex is not formed at detectable levels.[8]

In eukaryotes, overexpression of translation initiation factor 4E (eIF4E) leads to an increased level of cyclin D protein and increased amount of cyclin D mRNA outside of the nucleus. [9] This is because eIF4E promotes the export of cyclin D mRNAs out of the nucleus.[10]

Inhibition of cyclin D via i.a. inactivation or degradation leads to cell cycle exit and differentiation. Inactivation of cyclin D is triggered by several cyclin-dependent kinase inhibitor protein (CKIs) like the INK4 family (e.g. p14, p15, p16, p18). INK4 proteins are activated in response to hyperproliferative stress response that inhibits cell proliferation due to overexpression of e.g. Ras and Myc. Hence, INK4 binds to cyclin D- dependent CDKs and inactivates the whole complex.[3] Glycogen synthase kinase three beta, GSK3β, causes Cyclin D degradation by inhibitory phosphorylation on threonine 286 of the Cyclin D protein.[11] GSK3β is negatively controlled by the PI3K pathway in form of phosphorylation, which is one of several ways in which growth factors regulate cyclin D. Amount of cyclin D in the cell can also be regulated by transcriptional induction, stabilization of the protein, its translocation to the nucleus and its assembly with Cdk4 and Cdk6.[12]

It has been shown that the inhibition of cyclin D (cyclin D1 and 2, in particular) could result from the induction of WAF1/CIP1/p21 protein by PDT. By inhibiting cyclin D, this induction also inhibits Ckd2 and 6. All these processes combined lead to an arrest of the cell in G0/G1 stage.[5]

There are two ways in which DNA damage affects Cdks. Following DNA damage, cyclin D (cyclin D1) is rapidly and transiently degraded by the proteasome. This degradation causes release of p21 from Cdk4 complexes, which inactivates Cdk2 in a p53-independent manner. Another way in which DNA damage targets Cdks is p53-dependent induction of p21, which inhibits cyclin E-Cdk2 complex. In healthy cells, wild-type p53 is quickly degraded by the proteasome. However, DNA damage causes it to accumulate by making it more stable.[3]

Regulation in yeast[edit]A simplification in yeast is that all cyclins bind to the same Cdc subunit, the Cdc28. Cyclins in yeast are controlled by expression, inhibition via CKIs like Far1, and degradation byubiquitin-mediated proteolysis.[13]

Role in cancer[edit]

Given that many human cancers happen in response to errors in cell cycle regulation and in growth factor dependent intracellular pathways, involvement of cyclin D in cell cycle control and growth factor signaling makes it a possible oncogene. In normal cells overproduction of cyclin D shortens the duration of G1 phase only, and considering the importance of cyclin D in growth factor signaling, defects in its regulation could be responsible for absence of growth regulation in cancer cells. Uncontrolled production of cyclin D affects amounts of cyclin D-Cdk4 complex being formed, which can drive the cell through the G0/S checkpoint, even when the growth factors are not present.

Overexpression can happen in one of three ways: as a result of gene amplification, impaired protein degradation, or chromosomal translocation. Gene amplification is responsible for overproduction of cyclin D protein in bladder cancer and esophageal carcinoma, among others.[5]

In cases of sarcomas, colorectal cancers and melanomas, cyclin D overproduction is noted, however, without the amplification of the chromosomal region that encodes it

(chromosome 11q13, putative oncogene PRAD1, which has been identified as a translocation event in case of mantle cell lymphoma[14]). In parathyroid adenoma, cyclin D hyper-production is caused by chromosomal translocation, which would place expression of cyclin D (more specifically, cyclin D1) under an inappropriate promoter, leading to overexpression. In this case, cyclin D gene has been translocated to the parathyroid hormone gene, and this event caused abnormal levels of cyclin D.[5] The same mechanisms of overexpression of cyclin D is observed in some tumors of the antibody-producing B cells. Likewise, overexpression of cyclin D protein due to gene translocation is observed in human breast cancer.[5][15]

Additionally, the development of cancer is also enhanced by the fact that retinoblastoma tumor suppressor protein (Rb), one of the key substrates of cyclin D-Cdk 4/6 complex, is quite frequently mutated in human tumors. In its active form, Rb prevents crossing of the G1 checkpoint by blocking transcription of genes responsible for advances in cell cycle. Cyclin D/Cdk4 complex phosphorylates Rb, which inactivates it and allows for the cell to go through the checkpoint. In the event of abnormal inactivation of Rb, in cancer cells, an important regulator of cell cycle progression is lost. When Rb is mutated, levels of cyclin D and p16INK4 are normal. [5]

Another regulator of passage through G1 restriction point is Cdk inhibitor p16, which is encoded by INK4 gene. P16 functions in inactivating cyclin D/Cdk 4 complex. Thus, blocking transcription of INK4 gene would increase cyclin D/Cdk4 activity, which would in turn result in abnormal inactivation of Rb. On the other hand, in case of cyclin D in cancer cells (or loss of p16INK4) wild-type Rb is retained. Due to the importance of p16INK/cyclin D/Cdk4 or 6/Rb pathway in growth factor signaling, mutations in any of the players involved can give rise to cancer.[5]

Mutant phenotype[edit]

Studies with mutants suggest that cyclins are positive regulators of cell cycle entry. In yeast, expression of any of the three G1 cyclins triggers cell cycle entry. Since cell cycle progression is related to cell size, mutations in Cyclin D and its homologues show a delay in cell cycle entry and thus, cells with variants in cyclin D have bigger than normal cell size at cell division.[16][17]

p27−/− knockout phenotype show an overproduction of cells because cyclin D is not inhibited anymore, while p27−/− and cyclin D−/− knockouts develop normally.[16]

See also[edit]

CDK Cyclins Cell cycle

References[edit]

1. Jump up ̂  PDB: 2W96; Day PJ, Cleasby A, Tickle IJ, O'Reilly M, Coyle JE, Holding FP, McMenamin RL, Yon J, Chopra R, Lengauer C, Jhoti H (March 2009). "Crystal structure of human CDK4 in complex with a D-type cyclin". Proc. Natl. Acad. Sci. U.S.A. 106 (11): 4166–70. doi:10.1073/pnas.0809645106. PMC 2657441. PMID 19237565.

2. Jump up ̂  cyclin D - Protein - NCBI3. ^ Jump up to: a  b c Madame Curie Bioscience Database. Eurekah Bioscience

Database. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A20842#A20847

4. ^ Jump up to: a  b Hardwick JM (November 2000). "Cyclin' on the viral path to destruction". Nat. Cell Biol. 2 (11): E203–4. doi:10.1038/35041126. PMID 11056549.

5. ^ Jump up to: a  b c d e f g Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Ganler TS, Holland JF, Frei E (2003). Cancer medicine 6. Hamilton, Ont: BC Decker. ISBN 1-55009-213-8.

6. Jump up ̂  Resnitzky D, Reed SI (July 1995). "Different roles for cyclins D1 and E in regulation of the G1-to-S transition". Mol. Cell. Biol. 15 (7): 3463–9. PMC 230582. PMID 7791752.

7. Jump up ̂  Assoian RK, Klein EA (July 2008). "Growth control by intracellular tension and extracellular stiffness". Trends Cell Biol. 18 (7): 347–52. doi:10.1016/j.tcb.2008.05.002. PMC 2888483.PMID 18514521.

8. Jump up ̂  Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ (March 1999). "The p21Cip1 and p27Kip1 CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts". The EMBO Journal 18 (6): 1571–1583. doi:10.1093/emboj/18.6.1571.

9. Jump up ̂  Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N, London IM (September 1995). "Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels.". J Biol Chem 270: 21176–21180. doi:10.1074/jbc.270.36.21176. PMID 7673150.

10. Jump up ̂  Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KLB (April 2005). "eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR". J Biol Chem 169: 245–256. doi:10.1083/jcb.200501019. PMID 15837800.

11. Jump up ̂  Diehl JA, Cheng M, Roussel MF, Sherr CJ (November 1998). "Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization". Genes Dev 12 (22): 3499–3511.doi:10.1101/gad.12.22.3499. PMID 9832503.

12. Jump up ̂  Takahashi-Yanaga F, Sasaguri T (April 2008). "GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy". Cell. Signal. 20 (4): 581–9. doi:10.1016/j.cellsig.2007.10.018.PMID 18023328.

13. Jump up ̂  Bloom J, Cross FR (February 2007). "Multiple levels of cyclin specificity in cell-cycle control". Nat. Rev. Mol. Cell Biol. 8 (2): 149–60. doi:10.1038/nrm2105. PMID 17245415.

14. Jump up ̂  cyclin D1 Antibody (DCS-6) | Santa Cruz Biotech15. Jump up ̂  Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J

(1999). Molecular cell biology. New York: Scientific American Books. ISBN 0-7167-3136-3.

16. ^ Jump up to: a  b D.H. Sanes, T.A. Reh, W.A. Harris (2005). Development of the Nervous System (2 ed.). Elsevier Ltd, Oxford. ISBN 978-0126186215.

17. Jump up ̂  Geng Y, Yu Q, Sicinska E, Das M, Bronson RT, Sicinski P (January 2001). "Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice". Proc. Natl. Acad. Sci. U.S.A. 98 (1): 194–9. doi:10.1073/pnas.011522998. PMC 14567. PMID 11134518.

Cyclin EFrom Wikipedia, the free encyclopedia

cyclin E1

Identifiers

Symbol CCNE1

Alt. symbols CCNE

Entrez 898

HUGO 1589

OMIM 123837

RefSeq NM_001238

UniProt P24864

Other data

Locus Chr. 19 q12

cyclin E2

Identifiers

Symbol CCNE2

Entrez 9134

HUGO 1590

OMIM 603775

RefSeq NM_057749

UniProt O96020

Other data

Locus Chr. 8 q22.1

Cyclin E is a member of the cyclin family.

Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines cell division. The Cyclin E/CDK2 complex phosphorylates p27Kip1 (an inhibitor of Cyclin D), tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase.

Contents  [hide] 

1   Functions of Cyclin E 2   Cyclin E and Cancer

3   References 4   External links

Functions of Cyclin E[edit]

Like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase (CDK2). Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.

Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase.[1]Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression.[2] CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression.[3] Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression.[4]

Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication. [5] CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation.[6] Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.[7]

Cyclin E and Cancer[edit]

Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer.[8] Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.[9][10]

Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression.[11] Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination.[12] Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.

Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor.[13] Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer.[14] These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer.[15] Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy.[16]

Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas.[17] In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.[18]

Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis.[19]

References[edit]

1. Jump up ̂  Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992, 70: 993-1006

2. Jump up ̂  Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines. Cell Cycle. 2010, 9: 4900-4907

3. Jump up ̂  Morris L, Allen KE, La Thangue NB. Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. Nat Cell Biol. 2000, 2: 232-239

4. Jump up ̂  Ma T, Van Tine BA, Wei Y, et al. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev. 2000, 14: 2298-2313

5. Jump up ̂  Okuda M, Horn HF, Tarapore P, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000, 103: 127-140

6. Jump up ̂  Chen Z, Indjeian VB, McManus M, et al. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell. 2002, 3: 339-350

7. Jump up ̂  Huang H, Regan KM, Lou Z, et al. Cdk2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 2006, 314: 294-297

8. Jump up ̂  Donnellan R and Chetty R. Cyclin E in human cancers. FASEB J. 1999, 13: 773-780

9. Jump up ̂  Minella AC, Loeb KR, Knecht A, et al. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev. 2008, 22: 1677-1689

10.Jump up ̂  Kossatz U, Breuhahn K, Wolf B, et al. The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. J Clin Invest. 2010, 120: 3820-3833

11.Jump up ̂  Geisen C, Moroy T. The oncogenic activity of cyclin E is not confirmed to Cdk2 activation alone but relies on several other, distinct functions of the protein. J Biol Chem. 2002, 277: 39909-39918

12.Jump up ̂  Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993, 8: 2127-2133

13.Jump up ̂  Keyomarsi K, O’Leary N, Molnar G, et al. Cyclin E, a potential prognostic marker for breast cancer. Cancer Research. 1994. 54: 380-385.

14.Jump up ̂  Wingate H, Puskas A, Duong M, et al. Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression. Cell Cycle. 2009, 8: 1062-1068

15.Jump up ̂  Keyomarsi K, Tucker SL, Buchholz TA, et al. Cyclin E and survival in patients with breast cancer. NEJM 2002, 347: 1566-1575

16.Jump up ̂  Scaltriti M, Eichhorn PJ, Cortes J, et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. PNAS. 2011, 108: 3761-3766

17.Jump up ̂  Yasui W, Akama Y, Kuniyasu H, Yokozaki H, et al. Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status. Exp Ther Oncol. 1996, 1: 88-94

18.Jump up ̂  Kitahara K, Yasui W, Kuniyasu H, et al. Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas. Int. J. Cancer. 1995, 62: 25-28

19.Jump up ̂  Huang L, Wang D, Chen Y, et al. Meta-analysis for cyclin E in lung cancer survival. Clinica Chimica Acta. 2012, 413: 663-668

p53From Wikipedia, the free encyclopedia

For other uses, see P53 (disambiguation).

Tumor protein p53

PDB rendering based on 1TUP: P53 complexed with DNA[1]

Available structures

PDB Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

Symbols TP53 ; BCC7; LFS1; P53; TRP53

External

IDs

OMIM: 191170 MGI: 98834 HomoloGene: 46

0 ChEMBL : 4096 GeneCards: TP53 Gene

[show]Gene ontology

RNA expression pattern

More reference expression data

Orthologs

Species Human Mouse

Entrez 7157 22059

Ensembl ENSG00000141510 ENSMUSG00000059552

UniProt P04637 P02340

RefSeq

(mRNA)

NM_000546 NM_001127233

RefSeq

(protein)

NP_000537 NP_001120705

Location

(UCSC)

Chr 17:

7.66 – 7.69 Mb

Chr 11:

69.58 – 69.59 Mb

PubMe

dsearch

[1] [2]

v

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Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor.[2] As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.[3] Hence TP53 is classified as a tumor suppressor gene.[4][5][6][7][8] The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton (kDa) protein. However, the actual mass of the full length p53 protein (p53α) based on the sum of masses of theamino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. [9] In addition to the full length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa. All these p53 proteins are called the p53 isoforms.[2] The International Cancer Genome Consortium has established that the TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation.[2] TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.[10]

Contents  [hide] 

1   Gene 2   Structure 3   Function 4   Regulation 5   Role in disease 6   Experimental analysis of p53 mutations 7   Discovery 8   Isoforms 9   Interactions 10   Interactive pathway map 11   Peto's paradox 12   References

13   External links

Gene[edit]

In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1).[4][5][6][7] The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53.[11] TP53 orthologs [12]  have been identified in most mammals for which complete genome data are available.

In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.[13] A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.[14] A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.[15] One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.[16] A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.[17]

Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk[18] and endometrial cancer risk.[19] A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer.[20] Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.[21]

(Italics   are used  to denote the TP53 gene name and distinguish it from the protein it encodes.)

Structure[edit]

A schematic of the known protein domains in p53. (NLS = Nuclear Localization Signal).

Crystal structure of four p53 DNA binding domains (as found in the bioactive homo-tetramer) attand has seven domains:

1. an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors: residues 1-42. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes.[22]

2. activation domain 2 (AD2) important for apoptotic activity: residues 43-63.3. Proline  rich domain important for the apoptotic activity of p53 by nuclear exportation

via MAPK: residues 64-92.4. central DNA-binding core domain (DBD). Contains one zinc atom and

several arginine amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3.[23]

5. nuclear localization signaling domain, residues 316-325.6. homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for

the activity of p53 in vivo.7. C-terminal  involved in downregulation of DNA binding of the central domain: residues

356-393.[24]

A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53.[25] KO mutations  and position for p53 interaction with TFIID are listed below:[26]

9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA).[27][28]

Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53.

Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner.[29]

Function[edit]

p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms:

It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.[30]

It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).

It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable.

p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a,[31] WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.

When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.[32] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.[33]

Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.[34]

p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans.[35]

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading totanning.[36][37]

Regulation[edit]

p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[38] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.

The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to theMAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by theproteasome. However, ubiquitylation of p53 is reversible.

The novel molecule MI-63 binds to MDM2 making the action of p53 again possible in situations were p53's function has become inhibited.[39]

A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.[40]

Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.

USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cyptoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.[41]

Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 andSirt7, can deacetylate p53, leading to an inhibition of apoptosis.[42] Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.

Role in disease[edit]

Overview of signal transduction pathways involved in apoptosis.

A micrograph showing cells with abnormal p53 expression (brown) in a brain tumor. p53 immunostain.

If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of theTP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome.

The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.[43] Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.[44]

Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging.[45] Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.[46][46][47] The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus.[48]

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous

lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.[49]

The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.[50]

Experimental analysis of p53 mutations[edit]

Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects.[50]

The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provides cancer stem cell potential in different tissues.[51][52][53]

[54]

The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This "damped" oscillation is both clinically documented [55] and mathematically modelled.[56][57] Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such asdouble-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery.

Discovery[edit]

p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively. Independently, by Michel Kress and Pierre May, José A. Melero and Varda Rotter. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982,[58] and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).[59][60]The human TP53 gene was cloned in 1984[4] and the full length clone in 1985.[61]

It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine.[62]

Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[63] In a series of publications in 1991–92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.[64]

In 1993, p53 was voted molecule of the year by Science magazine.[65]

The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein.

Isoforms[edit]

As 95% of human genes, TP53 encodes more than one protein. In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone.[8]

The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the Proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a Proline and X can be any amino acid). It is required among others for p53 mediated apoptosis.[66] Some isoforms lack the Proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene.[67] Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain.

The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which leak the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms.[8]

Due to the isoformic nature of p53 proteins, there has been several evidences showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental Analysis of p53 mutations for more details).