Cell cycle control

Cell cycle phases

Cell cycle phases

M phase

S phase

G1 phase

G2 phase

Interphase

G1 + G2 + S

G1 checkpoint

Principal checkpoint

Passage through G1 checkpoint triggers entry into S phase

Most interphase cells are arrested at this point

G2 checkpoint

Controls entry into mitosis

Passage through G2 checkpoint triggers entry into M phase

Growth factors

External signals that act at the checkpoints to affect the cell cycle in one of two ways

-Promote cell proliferation

-Inhibit cell proliferation

Mechanism of Cell cycle control

The cell cycle is controlled by cycles of activation and inactivation of key control proteins

The enzymatic reactions are mediated by a specific set of protein kinases and protein phophatases

The activities of these enzymes rise and fall cyclically, in synchrony with the cell cycle

Enzyme activity controlled by cyclins

Control proteins

Responsible for cyclical activity of enzymes

cyclin dependent protein kinases (CDKS)

enzymes controlled by cyclins

EXP: M-cyclin: helps drive cells into M phase by acting in G2

M-Cdk

Relatively constant concentration

Activity varies depending on the concentration of the appropriate cyclin

M-cyclin helps drive cells into M phase

Concentration of cyclins rises gradually during the cell cycle and their rapid elimination initiates the exit from one phase and progression to the next

Activation of M-cyclin-Cdk complex

Two steps required to activate M-cyclin-Cdk complex

Phosphorylation of cyclin kinase at multiple sites

Dephosphorylation of MPF kinase at one or more inhibitory sites

Active M-cyclin complex stimulates dephosphorylation and activation of additional M-cyclin-Cdk copmlexes
- leads to immediate activation of all complexes and stimulation of mitosis

Other Cyclin-Cdk complexes

There are different sets of cyclins and Cdks involved in the control of the cell cycle at different checkpoints

S phase cyclins

Bind to Cdks in late G1

Trigger entry into S phase

G1 cyclins

Binds to Cdks in mid to late G1

initiate the formation and activation of S-phase cyclin-Cdk complexes

Activated by external growth factors

Concentration of each type of cyclin rises gradually, and then falls sharply, at the specific time in the cell cycle

Cdks remain inhibited throughout most of G1

- Several mechanisms prevent Cdk reactivation during G1

- Leads to a delay in progression into S phase and gives time to grow

Cell cycle arrest

The cell cycle can be arrested at any checkpoint

- To allow earlier steps in the cycle to be completed

- To await an external signal

G1 Arrest due to DNA damage

DNA damage leads to an increase in the concentration and activity of p53 (a gene regulatory protein)

Leads to activaiton of p21 gene transcriptio n
- production of p21, a Cdk inhibitor protein

- A stop in the cell cycle until the damage can be repaired

G0 arrest

cells that are not actively dividing can enter a temporary or permanent state of cell cycle arrest

G0: a resting phase characteristic of highly differentiated (specialized) cells and slowly growing cells

G0

For some cells, G0 is a permanent condition
- Neurons
- Skeletal muscle cells

For most cells, G0 is a temporary condition

G0 results from the partial dismantling of the cell cycle control system
- Disappearance of many Cdk proteins
- Disappearance of many cyclins

Mechanism of cell cycle control

Cell cycle is controlled by cycles of activation (by phosphorylation) and inactivation (by dephosphorylation) of key control proteins

These reactions are controlled by a specific set of protein kinases and protein phosphatases

Cyclin-dependent protein kinases

Enzymes that are controlled by cyclins

[] of cyclins rises gradually during the cell cycle and their rapid elimination initiates the exit from one phase and progression to the next

CDK activity

M-cyclin

Synthesis starts immediately after cell division and continues steadily during interphase and is at highest level just before mitosis

Sudden fall in M-cyclin concentration towards the end of mitosis due to rapid M-cyclin destruction

Destruction of M-cyclin inactivates M-CDK

Activation of M-cyclin-Cdk complex

Phosphorylation of cyclin kinase at multiple cites

Dephosphorylation of MPF kinase at inhibitory sites

Active M-cyclin-CDK complex stimulates dephosphorylation and activation of additional M-cyclin-CDK complexes leads to immediate activation of all complexes and stimulation of mitosis