Cell Cycle

• Who has a bigger cell? Elephant or Mouse?

• Why do cells divide instead of just growing bigger?– The larger the cell, the more demands it

places on DNA• Small cells, the DNA can meet the needs of the cell• As cell grows, the DNA can not meet the needs of

the cell – does not make extra copies of DNA to meet needs

Cell Size

• The larger the cell, the more difficult it is to transport nutrients and waste across the cell membrane. The cell membrane’s inefficiency increases– Exchange rate of materials is dependent on

the surface area• S.A. = Length X Width X # of sides

– The rate of materials used and waste produced is dependent on volume

• Volume = Length X Width X Height

• Understanding the relationship between surface area to volume is the key to understanding why cells must divide as they grow

The Cell CycleThe Cell Cycle (Movie)

• Normal growth, development, and maintenance depend on the timing and rate of mitosis (cell division). Various cells differ in their pattern of cell division:

• Human skin cells → frequent• Liver cells → only in appropriate situations• Nerve cells → do not divide in mature

humans

AP Biology

G2

S G1

Mmetaphase

prophase

anaphasetelophas

e

interphase (G1, S, G2 phases)mitosis (M)cytokinesis (C)

C

▪ Frequency of cell division varies by cell type◆ embryo

▪ cell cycle < 20 minute◆ skin cells

▪ divide frequently throughout life▪ 12-24 hours cycle

◆ liver cells▪ retain ability to divide, but keep it in reserve▪ divide once every year or two

◆ mature nerve cells & muscle cells▪ do not divide at all after maturity▪ permanently in G0

Frequency of cell division

Fig. 12-5

S(DNA synthesis)

MITOTIC(M) PHASE

Mitosi

sCytokinesis

G1

G2

Checkpoints

• The cell cycle is regulated by a molecular signaling system which switches the cell cycle control system on/off.

• The system consists of a molecular clock and checkpoints to ensure conditions are met before moving on to the next steps.

• Malfunctions may lead to cancer.

AP Biology

Overview of Cell Cycle Control▪ Two irreversible points in cell cycle◆ replication of genetic material◆ separation of sister chromatids▪ Checkpoints ◆ process is assessed & possibly halted

centromere

sister chromatids

single-strandedchromosomes double-stranded

chromosomes

There’s noturning back,now!

✓ ✓

Fig. 12-14

SG1

M checkpoint

G2M

Controlsystem

G1 checkpoint

G2 checkpoint

Cycle Phases

• G1 – First growth phase. Metabolic activity proceeds at a normal rate. Duration highly variable. Synthesis of enzymes related to DNA replication.

• G0 – Quiescent (rest) state. Usually for non-proliferative cells. Can occur for cells that are damaged. Alternative to apoptosis. Can be temporary or permanent.

• Nerve and muscle cells (multinucleated)

• S – DNA replication. – All chromosomes replicated. – Chromosomes consist of 2 sister chromatids in

chromatin form. – Histones produced.Chromosome

• 1 long string of DNA Sister chromatids

• Loose- chromatin• Tight - chromatid

Fig. 12-4 0.5 µm Chromosomes

Chromosomeduplication(including DNAsynthesis)

Chromo-some arm

Centromere

Sisterchromatids

DNA molecules

Separation ofsister chromatids

Centromere

Sister chromatids

• G2 – Second growth phase. – Reproduction of some organelles. High microtubule

production. – Two centrosomes. Aster around each centrosome.

Cells grow in size.• M – Mitosis.

– Prophase, Prometaphase, Metaphase, Anaphase, Telophase

• Cytokinesis– Birth of 2 daughter cells

Fig. 12-7

Microtubules Chromosomes

Sisterchromatids

Aster

Metaphaseplate

Centrosome

Kineto-chores

Kinetochoremicrotubules

Overlappingnonkinetochoremicrotubules

Centrosome 1 µm

0.5 µm

Internal and External Signals for Mitosis

• Growth Factors• Density-dependent inhibition

– Crowded cells stop dividing• Anchorage dependence

– Must be attached to … • ECM or culture of a jar

The Cell Cycle Clock/Checkpoints2 Types of Regulatory Molecules, together act as a

checkpoint1) Kinases– Amount doesn’t fluctuate– enzymes that phosphorylates molecules– Cyclin dependent kinase (Cdk) – inactive (G1 & G2) until cyclin

are present 2) Cyclins

– Molecule concentration fluctuates (unlike kinase)– Bonds w/ Kinase and serves a checkpoint– Cyclin-Cdk complex (MPF M-phase promoting factor) promotes

certain activities that eventually lead to the next stage of the cell cycle

– Having the minimum concentration of these complexes help the cell cycle proceed through the checkpoints

Actual Checkpoints

• Click on normal cell division (top left)

Steps of the Cell Cycle

• Sometime after cytokinesis G1 cyclins rise and bind to their Cdks (activates Cdks) which signals the cell to prepare for chromosome replication.– This moves cell past G1 checkpoint

• “S” phase promoting factor (SPF) enters the nucleus, prepares the cell to duplicate its DNA and centrosomes – S phase begins -

• S-cyclin-Cdk complexes form. They phosphorylate proteins that ensure DNA replication.

Fig. 12-17M G1 S G2 M G1 S G2 M G1

MPF activity

Cyclinconcentration

Time(a) Fluctuation of MPF activity and cyclin concentration

during the cell cycle

Degradedcyclin

Cdk

G 1S

G 2

M

CdkG2checkpointCyclin is

degraded

CyclinMPF

(b) Molecular mechanisms that help regulate the cell cycle

Cyclin accum

ulation

In depth Animation• During G2, M-phase cyclins begin to rise and form

Mitosis promoting factors (MPF) (M cyclin Cdk complexes).

• G2 checkpoint: Checks for DNA damage. • Then MPF initiates assembly of mitotic spindle, the

breakdown of the nuclear envelope, cessation of gene transcription, and condensation of the chromosomes, and taking the cell cycle all the way to metaphase.

• M checkpoint: All chromosomes are aligned at the metaphase plate,

• MPF activates the Anaphase Promoting Complex (APC) which allows sister chromatids to separate which activates G1 cyclins, and degrades M cyclins.

Quality Control• Systems for interrupting the cell cycle if

something goes wrong1) DNA damage checkpoint

1) happens at G1 checkpoint + S phase + M phase2) P53 gene – tumor suppresor

2) Completion of S-phase1) Makes sure that there are no okazaki fragments

3) Spindle Checkpoint1) Assures spindles are properly connected to

kinetichore• If problem cannot be fixed, the cell signals for

apoptosisIf problem cannot be fixed, the cell signals for apoptosis - Movie

Cancer• A group of diseases that involve irregular growth

and reproduction of cells• Cancer occurs when genes involved in the cycle,

specifically with check points are altered (growth factors)

• Transformation – single cell converts to a cancer cell

• Benign Tumor – a group of abnormal cells that does not invade other body systems- not considered cancerous

• Metastasis – when cancerous cells break off the original tumor and travel to other parts of the body

• Malignant Tumor – a tumor that invades a body system by traveling via the bloodstream or the lymphatic system

• Cancer causes death b/c the cells take over the function of organs

• Cancer arises due to damage to genes (90%) or inheritance (10)

Fig. 12-20

Tumor

A tumor growsfrom a singlecancer cell.

Glandulartissue

Lymphvessel

Bloodvessel

Metastatictumor

Cancercell

Cancer cellsinvade neigh-boring tissue.

Cancer cells spreadto other parts ofthe body.

Cancer cells maysurvive andestablish a newtumor in anotherpart of the body.

1 2 3 4

AP Biology

Growth Factors and Cancer▪ Growth factors can create cancers◆ proto-oncogenes

▪ normally activates cell division • growth factor genes • become Oncogenes (cancer-causing) when mutated

▪ if switched “ON” can cause cancer▪ example: RAS (activates cyclins)

◆ Tumor Suppressor Genes ▪ normally inhibits cell division▪ if switched “OFF” can cause cancer. Why?▪ example: p53

AP Biology

Cancer & Cell Growth▪ Cancer is essentially a failure

of cell division control ◆ unrestrained, uncontrolled cell growth

▪ What control is lost?◆ lose checkpoint stops◆ gene p53 plays a key role in G1/S restriction point

▪ p53 protein halts cell division if it detects damaged DNA • options:

■ stimulates repair enzymes to fix DNA ■ forces cell into G0 resting stage■ keeps cell in G1 arrest ■ causes apoptosis of damaged cell

▪ ALL cancers have to shut down p53 activity▪ Inhibits blood vessel growth in tumors (angiogenesis)

p53 discovered at Stony Brook by Dr. Arnold Levine

p53 is theCell CycleEnforcer

AP Biology

DNA damage is causedby heat, radiation, or chemicals.

p53 allows cellswith repairedDNA to divide.

Step 1

DNA damage iscaused by heat,radiation, or chemicals.

Step 1

Step 2

Damaged cells continue to divide.If other damage accumulates, thecell can turn cancerous.

Step 3p53 triggers the destruction

of cells damaged beyond repair.

ABNORMAL p53

NORMAL p53

abnormalp53 protein

cancercell

Step 3

The p53 protein fails to stopcell division and repair DNA.Cell divides without repair todamaged DNA.

Cell division stops, and p53 triggers enzymes to repair damaged region.

Step 2

DNA repair enzymep53protein p53

protein

p53 — master regulator gene

AP Biology

Development of Cancer▪ Cancer develops only after a cell experiences

~6 key mutations (“hits”)◆ unlimited growth

▪ turn on growth promoter genes◆ ignore checkpoints

▪ turn off tumor suppressor genes (p53)◆ escape apoptosis

▪ turn off suicide genes◆ immortality = unlimited divisions

▪ turn on chromosome maintenance genes◆ promotes blood vessel growth

▪ turn on blood vessel growth genes◆ overcome anchor & density dependence

▪ turn off touch-sensor gene

It’s like anout-of-contro

lcar with many

systems failing!

AP Biology

What causes these “hits”? ▪ Mutations in cells can be triggered by

◆ UV radiation◆ chemical exposure◆ radiation exposure◆ heat

◆ cigarette smoke◆ pollution◆ age◆ genetics

AP Biology

Tumors▪ Mass of abnormal cells◆ Benign tumor

▪ abnormal cells remain at original site as a lump

• p53 has halted cell divisions▪ most do not cause serious problems &

can be removed by surgery◆ Malignant tumor

▪ cells leave original site• lose attachment to nearby cells • carried by blood & lymph system to other tissues• start more tumors = metastasis

▪ impair functions of organs throughout body

Mitosis

• Mitosis – reproduction of the nucleus• Cytokinesis – division of the cytoplasm• Diploid (2n) – cells that have 2 sets of

chromosomes (46)• Haploid (n) - cells that have 1 set of

chromosomes (23)• Somatic cells – cells that only undergo

mitosis

Diploid – 2n

• M1 + D1 are homologous• Zygote = egg + sperm

• Allele: different versions of the same trait

m1 m2 m3 D1 D2 D3

• During G2 -Tetraploid – 4n

46 – double stranded chromosomes

m1 m1 D1 D1

• Egg and Sperm produced in Meiosis (haploid)

+Egg (n) Sperm (n)

Stage

• G1 – Diploid (2n)• S – Tetraploid (4n) Interphase• G2 – Tetraploid• Mitosis…

Prophase-

-Chromatin fibers begin to condense into chromosomes and wind around histone proteins.

-Nucleoli disappears.

-Chromosomes become visible. Chromatid arms held together by cohesions (vertebrates only at the centromere).

-Mitotic spindle forms, extending from the centrosomes outside the nucleus forming asters. Centrioles (found in animal and lower plant cells) are in the center of the centrosome.

-The centrosomes are moving to opposite poles.

Prometaphase

-The nuclear envelopes fragments and nucleolus is not longer visible.

-Centrosomes are at opposite ends of the nuclear area.

-The microtubules extend through the nuclear area

-2 Kinetochores (facing opposite from one another) form on the centromere. These are protein structures that allow microtubules to attach.

-Kinetochore microtubules attach to the kinetochores. Moving the chromosomes back and forth until they reach the middle of the cell.

Metaphase-

-Longest phase of mitosis.

-The “tug and pull” of the kinetochore microtubules brings the twin chromatids to the metaphase plate.

Anaphase-

-Cohesion proteins are cleaved and the sister chromatids separate. The chromatids become chromosomes in their own right.

-The chromosomes begin to move to opposite poles. The chromosomes are “walking” up the kinetochore microtubules.

-The kinetochore microtubules are disassembled at the chromosome end.

-The nonkinetochore microtubules move further apart as the interact with one another. More subunits are attached to the overlapping end. This causes the cell to enlarge.

This experiment shows that the microtubules are disassembled at the chromosome end and not the centrosome end. The spindle fiber were marked in the middle. If the microtubules shorten between the mark and centrosome, then the microtubules are being reeled in but if the microtubules shorten between the mark and the chromosomes, then microtubules are being disassembled at that end. The latter is the case. The kinetochore disassembles the microtubules at the chromosome end, as the chromosome “walks” up the microtubule.

Telophase

-Two daughter nuclei form in the cell.

-Nuclear envelope forms from the fragments of the disassembled nuclei and the endomembrane system.

-Chromosomes unwind forming chromatin.

-Beginning of cytokinesis

Cytokinesis

Mitosis without cytokinesis results in coencytic bodies without individual cells.

Happens in some plants, fungi, algae and even a few animals. Animals cells do cytokinesis by the pinching in of the cell membrane.

In animal cells, rings of actin form under the cell membrane associated with myosin (much like skeletal muscles) contracts like a “pull-string” purse. This forms a cleavage furrow.

Cell Plate in plant cells forms by fusing vesicles produced by the golgi

Fig. 12-9

Cleavage furrow100 μm

Contractile ring ofmicrofilaments

Daughter cells

(a) Cleavage of an animal cell (SEM) (b) Cell plate formation in a plant cell (TEM)

Vesiclesformingcell plate

Wall ofparent cell

Cell plate

Daughter cells

New cell wall

1 μm