Cell cycle

The cell cycle: cells duplicate their contents and divide

The cell cycle may be divided into 4 phases

The cell cycle triggers essential processes

(DNA replication, mitosis)

Progression of the cell cycle is regulated by feedback from intracellular events

Chemical Signals tell a cell

when to start and stop dividing.

Checkpoint control system

• Checkpoints

– cell cycle controlled by STOP & GO chemical signals at critical points

– signals indicate if key cellular processes have been completed correctly

Checkpoint control system

• 3 major checkpoints: – G1/S

• can DNA synthesis begin?

– G2/M

• has DNA synthesis been completed correctly?

• commitment to mitosis

– spindle checkpoint • are all chromosomes

attached to spindle?

• can sister chromatids separate correctly?

G1/S checkpoint

• G1/S checkpoint is most critical

– primary decision point

• “restriction point” it has two cases

“GO” signal if cell receives signal , it divides two types of signals

internal signals: cell growth (size), cell nutrition

external signals: “growth factors”

“No signal” if cell does not receive signal, it exits cycle & switches to G0 phase

non-dividing, working state

G1 PHASE S PHASE

G0 Phase

The cell cycle stops between G1 and S phase for checks to be made.

Any problems, the cycle enters G0 phase while the problem is sorted

Problems resolved, re-enter S phase

G0 phase

M

Mitosis

G1

Gap 1

G0

Resting

G2

Gap 2

S

Synthesis

• G0 phase

– non-dividing, differentiated state

– most human cells in G0 phase

liver cells

in G0, but can be

“called back” to cell

cycle by external cues

nerve & muscle cells

highly specialized;

arrested in G0 & can

never divide

G2 PHASE M PHASE

HALT!!!!! There has been a problem with the DNA transcription.I can not give you a pass (Cdk), you must wait here till the DNA is fixed!!!!

G2 PHASE M PHASE

STOP!!!!

Is your DNA replication complete?

Is your DNA intact??

If the DNA replication is complete and intact the cell can continue through the cycle.

Checkpoint Problems

• If checkpoints come across a problem

E.g.: DNA Damage

Produce Cdk inhibitor protein

Block/stop Cdk signals

• No passes are given out so there is no progression

• Cell does not move to next phase until repair is

complete

“Go-ahead” signals

1-Protein signals that promote cell growth & division

A. internal signals

“promoting factors”

B. external signals

• “growth factors”

2-Primary mechanism of control

–phosphorylation

• kinase enzymes

• either activates or inactivates cell signals

• Cell cycle controled by

a) cyclins

• regulatory proteins

• levels cycle in the cell

b) Cdk’s

• cyclin-dependent kinases

• phosphorylates cellular proteins

–activates or inactivates proteins

c) Cdk-cyclin complex

• triggers passage through different stages of cell cycle

Cell cycle signals

activated Cdk

inactivated Cdk

Cyclin & Cyclin-dependent kinases proteins

• CDKs & cyclin drive cell from one phase to next in cell cycle

Proper regulation of cell cycle is so key to life that the genes for these regulatory proteins have been highly conserved through evolution

The genes are basically the same in yeast, insects, plants & animals (including humans)

• CDK and cyclin together form an

enzyme that activates other proteins

by chemical modification

(phosphorylation).

• The amount of CDK molecules is

constant during the cell cycle, but

their activities vary because of the

regulatory function of the cyclins.

Cyclin & Cyclin-dependent kinases proteins

Cyclin D-CDK4

Cyclin E-CDK2

Cyclin A-CDK2

Cyclin B-CDC2

CDK

inhibitors

Cyclin and cyclin dependent kinases

map during cell cycle

Cancer how does it happen

• 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

p53 is the Cell Cycle Enforcer

Cancer • Tumor: abnormal mass of tissue that results

from lack of balance in cell division and apoptosis

– Benign: usually slow growing and harmless

– Malignant: invades adjacent tissue, more likely to metastasize

• Cancer cells are no longer under cell cycle control, daughter cells free of control, too

DNA damage is caused by heat, radiation, or chemicals.

p53 allows cells with repaired DNA to divide.

Step 1 Step 3

p53 triggers the destruction of cells damaged beyond repair.

NORMAL p53

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

Step 2

DNA repair enzyme p53 protein

p53 protein

p53 — master regulator gene (normal cell)

DNA damage is caused by heat, radiation, or chemicals.

Step 1 Step 2

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

ABNORMAL p53

abnormal p53 protein

cancer cell

Step 3 The p53 protein fails to stop cell division and repair DNA. Cell divides without repair to damaged DNA.

p53 — master regulator gene (Cancer cell)

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 an out of control car!