The Cell Cycle

The Cell Cycle

Dr. Jorge Rodríguez

Overview: The Key Roles of Cell Division

• The ability of organisms to produce more of their own kind best distinguishes living things from nonliving matter

• The continuity of life is based on the reproduction of cells, or cell division

© 2011 Pearson Education, Inc.

Cell division plays several important roles in life

• In unicellular organisms (proka- or eukaryotes), division of one cell reproduces the entire organism

• Multicellular organisms depend on cell division for

– Reproduction - Development from a fertilized cell– Growth and development– Repair of tissues

• Cell division is an integral part of the cell cycle, the life of a cell from formation to its own division


Figure 12.2

(a) Reproduction

(b) Growth and development

(c) Tissue renewal20 m

100 m

200 m

Amoeba, dividing into two cells

Sand dollar, embryo shortly after fertilized egg divided

Dividing bone marrow cells

Most cell division results in genetically

identical daughter cells

• Most cell division results in daughter cells with identical genetic information, DNA

• The exception is meiosis, a special type of division that can produce sperm and egg cells


Cellular Organization of the Genetic Material

• All the DNA in a cell constitutes the cell’s genome• A genome can consist of a single DNA molecule

(common in prokaryotic cells) or a number of DNA molecules (common in eukaryotic cells)

• Before the cell can divide this DNA must be copied or replicated and separated to two daughter cells


Figure 12.3

20 m

DNA molecules in a cell are packaged into chromosomes

Nucleus

Rough ER

Nucleolus

Chromatin

Nuclear envelope:

Inner membrane

Outer membrane

Nuclear pore

Chromatin

Ribosome

Porecomplex

Close-upof nuclearenvelope

Figure 6.9a

Eukaryotic chromosome consists of one very long, DNA molecule associated with proteins.

DNA molecule carries several hundreds to a few thousand genes

The associated proteins mantain the structure of the chromosome and help control the activities of the genes

Eukaryotic chromosomes consist of chromatin, a complex of DNA and protein that condenses during cell division

• Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus

• Somatic cells (body cells, nonreproductive cells) have two sets of chromosomes

• Gametes (reproductive cells: sperm and eggs) have half as many chromosomes as somatic cells


Distribution of Chromosomes During Eukaryotic Cell Division

• In preparation for cell division, DNA is replicated and the chromosomes condense

• Each duplicated chromosome has two sister chromatids (joined copies of the original chromosome), which separate during cell division– Attached along their lenghts by protein complex called

cohesins (cohesinas)


0.5 mCentromere

Sisterchromatids

One sisterchromatid

• The centromere is the narrow “waist” of the duplicated chromosome, where the two chromatids are most closely attached

• The part of a chromatid on either side of the centromere is referred to as arm of the chromatid


0.5 mCentromere

Sisterchromatids

• During cell division, the two sister chromatids of each duplicated chromosome separate and move into two nuclei

• Once separate, the chromatids are called chromosomes


Figure 12.5-3

ChromosomesChromosomal

DNA molecules

Centromere

Chromosomearm

Chromosome duplication(including DNA replication)and condensation. Two sister chromatids are formed

Sisterchromatids

Separation of sisterchromatids intotwo chromosomes

1

2

3

• Eukaryotic cell division consists of– Mitosis, the division of the genetic material in the

nucleus– Cytokinesis, the division of the cytoplasm

• Gametes are produced by a variation of cell division called meiosis

• Meiosis yields nonidentical daughter cells that have only one set of chromosomes, half as many as the parent cell


The mitotic phase alternates with interphase in the cell cycle

• In 1882, the German anatomist Walther Flemming developed dyes to observe chromosomes during mitosis and cytokinesis


Phases of the Cell Cycle

• The cell cycle consists of– Mitotic (M) phase (mitosis and cytokinesis)– Interphase (cell growth and copying of chromosomes in

preparation for cell division)– Mitosis is the shortest and interphase is the longer stage of the

cell cycle


• Interphase (about 90% of the cell cycle) can be divided into subphases

– G1 phase (“first gap”)

– S phase (“synthesis”)

– G2 phase (“second gap”)

• The cell grows during all three phases producing organelles, but chromosomes are duplicated only during the S phase


Figure 12.6

The cell cycleINTERPHASE

G1, first part of interphase, followed by S

G2

S(DNA synthesis and

chromosome duplication)

MITOTIC(M) PHASE

Cytokinesis

Mito

sis

MITOTIC (M) PHASE, alternate with interphase

• M phase, daughter cromosomes in daugther nuclei.• Cytokinesis, divide the cytoplasm into 2 daugther cells.• Relative duration of the phases may vary.

• Mitosis is conventionally divided into five phases– Prophase– Prometaphase– Metaphase– Anaphase– Telophase

• Cytokinesis overlaps the latter stages of mitosis completing the mitotic stages


Figure 12.7aG2 of Interphase Prophase Prometaphase

Centrosomes(with centriole pairs)

Chromatin(duplicated)

NucleolusNuclearenvelope

Plasmamembrane

Early mitoticspindle

AsterCentromere

Chromosome, consistingof two sister chromatids

Fragments of nuclearenvelope

Nonkinetochoremicrotubules

Kinetochore Kinetochoremicrotubule

• Sobre nuclear rodea el núcleo.

• Nucleoli (s) present.

• 2 centrosomas formados por duplicación de cada cromosoma. • Chromosomes not condensed.

• Chromatin become condensed.

• Nucleoli dissapear.

• Each chromosome appears as two sister chromatids.

• Mitotic spindle begins to form. Composed by centrosomes and microtubules.

• Asters, radial arrays of microtubules.

• Centrosomes move away.

• Envelope fragments.

• Microtubules invade nuclear area.

• Kinetochore appears at centromeres.

• Kinetochore microtubules forming.

• Nonkinetochore microtubules forms the opposite pole of the spindle.

Figure 12.7bMetaphase

Metaphase plate

Anaphase Telophase and Cytokinesis

Spindle Centrosome atone spindle pole

Daughterchromosomes

Cleavagefurrow

Nucleolusforming

Nuclearenvelopeforming

• Centrosomes at opposite poles of the cell.

• Chromosomes at metaphase plate.

• Shortest phase.

• Cohesins are cleaved.

• Sister chromatids separates.

• Daugther chromosomes moves towards opposite poles.

• Cell elongates.

• Two nuclei forms in the cell.

• Nuclear envelopes arises.

• Nucleoli reappear.

• Chromosomes less condensed.

• Depolymerization of microtubules.

• Mitosis is completed.

• Cytokinesis under way by late telophase. Formation of cleavage furrow.

Mitosis

Cytokinesis

MITOTIC (M) PHASE

G1

G2

S

Telophase andCytokinesis

AnaphaseMetaphase

Prometaphase

Prophase

I T R HASEE PNFigure 12.UN01

Figure 12.7a

G2 of Interphase Prophase Prometaphase




Plasmamembrane


Aster

Centromere





The Mitotic Spindle: A Closer Look

• Many events of mitosis depend on the mitotic spindle• Begins to form in the cytoplasm during prophase• The mitotic spindle is a structure made of fibers and associated proteins• The spindle polymerize by incorporating subunits of tubulin• Controls chromosome movement during mitosis

Figure 12.7a





Plasmamembrane


AsterCentromere






• In animal cells, assembly of spindle microtubules begins in the centrosome, a subcellular region the microtubule organizing center

– A pair of centrioles is located at the center of the centrosomes, not essential for cell division

• The centrosome replicates during interphase, forming two centrosomes • As spindle microtubules grows, centrosomes migrate to opposite ends of the

cell during prophase and prometaphase

Figure 12.7a





Plasmamembrane


AsterCentromere






• An aster (a radial array of short microtubules) extends from each centrosome

• The spindle includes the centrosomes, the spindle microtubules, and the asters

Figure 12.7a





Plasmamembrane


AsterCentromere






• During prometaphase, some spindle microtubules attach to the kinetochores of chromosomes and begin to move the chromosomes

Kinetochores microtubules• Kinetochores are protein complexes (2) associated with centromeres in each sister chromatids


Metaphase plate



Daughterchromosomes

Cleavagefurrow

Nucleolusforming


• At metaphase, the chromosomes are all lined up at the metaphase plate, an imaginary structure at the midway point between the spindle’s two poles

• The spindle is completed when microtubules of the asters attach to the plasma membrane

Figure 12.8

Sisterchromatids

AsterCentrosome

Metaphaseplate(imaginary)

Kineto-chores

Overlappingnonkinetochoremicrotubules Kinetochore

microtubules

Microtubules

Chromosomes

Centrosome

0.5 m

1 m

• At metaphase, the chromosomes are all lined up at the metaphase plate, an imaginary structure at the midway point between the spindle’s two poles

• The spindle is completed when microtubules of the asters attach to the plasma membrane

Figure 12.UN04


Metaphase plate



Daughterchromosomes

Cleavagefurrow

Nucleolusforming


• In anaphase, cohesins are cleaved by separases• Sister chromatids separate and move along the kinetochore

microtubules toward opposite ends of the cell• The microtubules shorten by depolymerizing at their kinetochore ends


Metaphase plate



Daughterchromosomes

Cleavagefurrow

Nucleolusforming


• In anaphase, nonkinetochore microtubules from opposite poles overlap and push against each other, elongating the cell

• At the end of anaphase, duplicate chromosomes have arrived at opposite ends of elongated parent cell

• In telophase, genetically identical daughter nuclei form at opposite ends of the cell

• Cytokinesis begins during anaphase or telophase and the spindle eventually disassembles by depolymerization

Cytokinesis: A Closer Look

• In animal cells, cytokinesis occurs by a process known as cleavage, forming a cleavage furrow (surco o hendedura)

• In plant cells, a cell plate forms during cytokinesis


Figure 12.10a(a) Cleavage of an animal cell (SEM)

100 mCleavage furrow (old metaphase plate)

Contractile ring of microfilaments (actin and myosin)

Daughter cells (cytosol, nucleus, organelles, subcellular structures)

Figure 12.10b

(b) Cell plate formation in a plant cell (TEM)

Vesiclesformingcell plate

Wall of parent cell

Cell plate New cell wall

Daughter cells

1 m

• No cleavage furrow formed.

• Telophase, vesicles from Golgi move to the middle of the cell, coalesce and produce a cell plate.

• Vesicles contains cell wall material and fuses with the plasma membrane.

• Two daugther cells result.

Binary Fission in Bacteria

• Prokaryotes (bacteria and archaea) reproduce by a type of cell division called binary fission

• In binary fission, bacteria grows and the chromosome replicates (beginning at the origin of replication), and the two daughter chromosomes actively move apart

• The plasma membrane pinches inward, dividing the cell into two

• Binary fission in single-celled eukaryotes such as amoeba


Figure 12.12-1

1

Origin ofreplication

E. coli cell

Two copies of origin

Cell wallPlasma membrane

Bacterial chromosomeChromosomereplicationbegins.

Chromosome replicates (beginning at the origin of replication), and the two daughter chromosomes actively move apart (not understood).

1


E. coli cell



Bacterial chromosome

Origin Origin

Chromosomereplicationbegins.

Replicationcontinues.

2

Figure 12.12-2

• One copy of each origin at each end of the cell.

• Cell elongates.

1


E. coli cell




Origin Origin



Replicationfinishes.

2

3

Figure 12.12-3

Plasma membrane grows inward, a new cell wall is formed.

1


E. coli cell




Origin Origin



Replicationfinishes.

Two daughtercells result.

2

3

4

Figure 12.12-4

The eukaryotic cell cycle is regulated by a molecular control system

• The frequency of cell division varies with the type of cell– Timing and rate of cell division are crucial to

growth, development and maintenance in different parts of the cell

• These cell cycle differences result from regulation at the molecular level

• Cancer cells manage to escape the usual controls on the cell cycle


Evidence for Cytoplasmic Signals

• The cell cycle appears to be driven by specific chemical signals present in the cytoplasm

• Some evidence for this hypothesis comes from experiments in which cultured mammalian cells at different phases of the cell cycle were fused to form a single cell with two nuclei


Figure 12.14

Experiment 1 Experiment 2

S

S S

G1 G1M

M M

EXPERIMENT

RESULTS

When a cell in the Sphase was fusedwith a cell in G1,the G1 nucleusimmediately enteredthe S phase—DNAwas synthesized.

When a cell in the M phase was fused witha cell in G1, the G1

nucleus immediatelybegan mitosis—a spindleformed and chromatincondensed, even thoughthe chromosome had notbeen duplicated.

Conclusion: The results of fusing a G1 with a S or M cell cycle suggest that molecules present in the cytoplasm during S or M phase control the progression to those phases.

The Cell Cycle Control System

• The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock

• The cell cycle control system is regulated by both internal and external controls

• The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received


G1 checkpoint

G1

G2

G2 checkpointM checkpoint

M

SControlsystem

Figure 12.15

Three major checkpoints: G1, G2, M phases

Figure 12.16

G1 checkpoint

G1 G1

G0

(a) Cell receives a go-ahead signal.

(b) Cell does not receive a go-ahead signal.

• For many cells, the G1 checkpoint seems to be the most important

• If a cell receives a go-ahead signal at the G1 checkpoint, it will usually complete the S, G2, and M phases and divide

• If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a nondividing state called the G0 phase

The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases

• Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks)

• Cdks activity fluctuates during the cell cycle because it is controled by cyclins, so named because their concentrations vary with the cell cycle


Figure 12.17a

(a) Fluctuation of MPF activity and cyclin concentration during the cell cycle

MPF activityCyclinconcentration

Time

M M MS SG1 G2 G1 G2 G1

MPF (maturation-promoting factor) is a cyclin-Cdk complex that triggers a cell’s passage past the G2 checkpoint into the M phase

The peaks of MPF activity corresponds to the peaks of cyclin concentration. Cyclin level rises during the S and G2 , then falls during M phase.

Molecular mechanisms that help regulate the cell cycle

Cdk

Degradedcyclin

Cyclin isdegraded

MPF

G2checkpoint

Cdk

Cyclin

MS

G 1G 2

Figure 12.17b

1. Synthesis of cyclin begins in S and continue through G2.


Cdk

Degradedcyclin

Cyclin isdegraded

MPF

G2checkpoint

Cdk

Cyclin

M

SG 1

G 2

Figure 12.17b

2. Cyclin combines with Cdk, producing MPF.

MPF accumulate, the cell passes the G2 checkpoint and begins mitosis.


Cdk

Degradedcyclin

Cyclin isdegraded

MPF

G2checkpoint

Cdk

Cyclin

M

SG 1

G 2

Figure 12.17b

3. MPF phosphorylates various proteins.

MPF’s activity peaks during metaphase.


Cdk

Degradedcyclin

Cyclin isdegraded

MPF

G2checkpoint

Cdk

Cyclin

M

SG 1

G 2

Figure 12.17b

4. Anaphase, cyclin component of MPF is degraded, terminating M phase.

The cell enters G1.


Cdk

Degradedcyclin

Cyclin isdegraded

MPF

G2checkpoint

Cdk

Cyclin

M

SG 1

G 2

Figure 12.17b

5. G1, degradation of cyclin continues.Cdk component of MPF is recycled.


Cdk

Degradedcyclin

Cyclin isdegraded

MPF

G2checkpoint

Cdk

Cyclin

M

SG 1

G 2

Figure 12.17b

1. Synthesis of cyclin begins in S and continue through G2.

2.Cyclin combines with Cdk, producing MPF.

MPF accumulate, the cell passes the G2 checkpoint and begins mitosis.

3. MPF phosphorylates various proteins.

MPF’s activity peaks during metaphase.

4. Anaphase, cyclin component of MPF is degraded, terminating M phase.

The cell enters G1.

5. G1, degradation of cyclin continues.Cdk component of MPF is recycled.

Stop and Go Signs: Internal and External Signals at the Checkpoints

• An example of an internal signal is that kinetochores not attached to spindle microtubules send a molecular signal that delays anaphase

• Some external signals are growth factors, proteins released by certain cells that stimulate other cells to divide

• For example, platelet-derived growth factor (PDGF) stimulates the division of human fibroblast (connective tissue) cells in culture


Figure 12.18

A sample of humanconnective tissue iscut up into smallpieces.

Enzymes digestthe extracellularmatrix, resulting ina suspension offree fibroblasts.

Cells are transferred toculture vessels.

Scalpels

Petridish

PDGF is addedto half thevessels.

Without PDGF With PDGF

10 m

1

2

3

4

• A clear example of external signals is density-dependent inhibition, in which crowded cells stop dividing

• Most animal cells also exhibit anchorage dependence, in which they must be attached to a substratum in order to divide

• Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence


Figure 12.19

Anchorage dependence, cells anchor to dish surface and divide.

Density-dependent inhibition, when cell have formed a single layer, crowded cells stop dividing

Density-dependent inhibition

(a) Normal mammalian cells

20 m

Figure 12.19

(b) Cancer cells

20 m

Cancer cells, exhibit neither density dependent inhibition nor anchorage dependence.

Loss of Cell Cycle Controls in Cancer Cells

• Cancer cells do not respond normally to the body’s control mechanisms

• Cancer cells may not need growth factors to grow and divide

– They may make their own growth factor– They may convey a growth factor’s signal without

the presence of the growth factor– They may have an abnormal cell cycle control

system


• A normal cell is converted to a cancerous cell by a process called transformation

• Cancer cells that are not eliminated by the immune system form tumors, masses of abnormal cells within otherwise normal tissue

• If abnormal cells remain only at the original site, the lump is called a benign tumor, not a serious problem

• Malignant tumors invade surrounding tissues and can metastasize, exporting cancer cells to other parts of the body, where they may form additional tumors


Figure 12.20

Glandulartissue

Tumor

Lymph vesselBloodvessel

Cancercell

Metastatictumor

A tumor growsfrom a singlecancer cell.

Cancer cells invade neighboringtissue.

Cancer cells spreadthrough lymph andblood vessels to other parts of the body.

Cancer cells may survive and establisha new tumor in another part of the body.

4321


• Recent advances in understanding the cell cycle and cell cycle signaling have led to advances in cancer treatment

• Tx: cell cycle specific inhibitors, monoclonal antibodies, etc

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