JM Lecture 52: Regulation of cell cycle progression

Question 1

Describe the Cdk phosphorylation of substrates for the G1 phase.

Answer 1

Kinase: Cdk4 and 6
Cyclin: D
Mechanism of increasing cyclin: Growth factor signaling
Substrate: pRb
Effect: Cyclin E increase

Question 2

Describe the Cdk phosphorylation of substrates for the G1-S phase.

Answer 2

Kinase: Cdk2
Cyclin: E
Mechanism of increasing cyclin: E2F release from Rb
Substrate: pRb
Effect: DNA pol increase etc. and Cyclin A increase

Question 3

Describe the Cdk phosphorylation of substrates for the S phase.

Answer 3

Kinase: Cdk2
Cyclin: A
Mechanism of increasing cyclin: E2F release from Rb
Substrate: polymerase complex and Cdc6/Orc1/Cdt1
Effect: origin of firing/block of re-initiation

Question 4

Describe the Cdk phosphorylation of substrates for the M phase.

Answer 4

Kinase: Cdk1
Cyclin: B
Mechanism of increasing cyclin: Loss of repressor
Substrate: lamins and condensin
Effect: nuclear membrane breakdown and chromatin condensation (respectively)

Question 5

What happens if the control of a checkpoint in the cell cycle is lost?

Answer 5

uncontrolled proliferation of cells (cancer)

Question 6

List the checkpoints of the cell cycle.

Answer 6

Restriction point (G1)
DNA damage checkpoints (G1-->S and G2-->S)
Unreplicated DNA Checkpoint (S-->G2)
Incomplete Spindle Formation Checkpoint (M)

Question 7

What mediates the Restriction point checkpoint in the cell cycle?

Answer 7

pRb phosphorylation in response to growth factors (growth factor signaling increases transcription of cyclin D which triggers phosphorylation of pRb and release of E2F)
connects extracellular signaling and cell-cycle control

Question 8

How does DNA damage regulate the cell cycle at the G1 checkpoint?

Answer 8

DNA damage causes up-regulation of the tumor suppressor p53
kinase cascade results in phosphorylation of p53 and Mdm2 (p53’s negative regulator) which disrupts binding and p53 levels rise
p53 is a transcription factor for p21 (cyclin-dependent kinase inhibitor) which binds to the Cdk complex and prevents phosphorylation of pRb leading to arrest prior to S phase
*note p53 can also cause apoptosis

Question 9

How does DNA damage regulate the cell cycle at the G2 checkpoint?

Answer 9

DNA damage triggers a kinase cascade
inhibits phosphorylation of Cdc25
no activation of Cyclin B/Cdk1

Question 10

Describe how unreplicated DNA regulates the cell cycle.

Answer 10

Cdc25 cannot be phosphorylated (active) until DNA synthesis is complete (4N DNA is achieved)

Question 11

Describe the spindle checkpoint.

Answer 11

disruption of the spindle (and a loss of attachment of microtubules to the kinetichore) causes delay in the activation of APC until all chromosomes are properly aligned in metaphase