Cell Cycle Control

Question 1

What are the phases of the cell cycle?

Answer 1

• M (mitosis)
• G1 (preparation for DNA replication)
• S (DNA synthesis)
• G2 (preparation for mitosis)

Also G0 (non-proliferating/quiescent cells sit here)

Question 2

What are the key regulators of transition between cell cycle phases?

Answer 2

Cyclin Dependant Kinases (CDKs)

Question 3

What are CDKs?

Answer 3

Serine/Theonine kinases - phosphorylate substrates at certain motifs contaning these

Question 4

What do CDK substrates do?

Answer 4

Promote cell cycle progression

Question 5

When are CDKs only active?

Answer 5

When they are bound to their partner cyclins

Question 6

How do CDK levels change during cell cycle?

Answer 6

They are relatively stable

Question 7

How do cyclin levels change during cell cycle?

Answer 7

They rise and fall to cause oscillation in CDK activation

Question 8

Which CDKs operate during G1?

Answer 8

CDK4-6

Question 9

Which Cyclins operate with CDK4-6?

Answer 9

Cycin D1, D2 and D3

Question 10

Which CDK operates during G1/S?

Answer 10

CDK2

Question 11

Which CDK operates during S phase?

Answer 11

CDK2

Question 12

Which CDK operates during Mitosis?

Answer 12

CDK1

Question 13

Which cyclins operate with CDK2 in G1/S?

Answer 13

Cyclin E1 and E2

Question 14

Which cyclins operate with CDK2 in S phase?

Answer 14

Cyclins A1 and A2

Question 15

Which cyclin operates with CDK1 in Mitosis?

Answer 15

Cyclin B1

Question 16

Which complex is essential for entry into G1?

Answer 16

CyclinD/CDK4-6

Question 17

What complexes regulate G1 to S progression?

Answer 17

CyclinE/CDK2

Question 18

What do CyclinA/CDK2 complexes do during S and G2?

Answer 18

Trigger DNA polymerase action

Question 19

What complex promotes entry into Mitosis?

Answer 19

CyclinA/CDK1

Question 20

What does the retinoblastoma protein normally do?

Answer 20

Inhibits progression through the cell cycle by inhibiting E2F transcription factor

Question 21

What initially phosphorylates Rb protein into its inactive form so that Cyclin E can be transcribed?

Answer 21

CyclinD/CDK4-6

Question 22

Which complex also phosphorylates Rb to completely inactivate it?

Answer 22

CyclinE/CDK2

Question 23

What does this complete phosphorylation of Rb result in?

Answer 23

E2F is not inhibited so S-Phase genes can be synthesised.

Question 24

What S-phase genes are pushed through by E2F?

Answer 24

• DNA synthesis
• DNA replication
• DNA repair
• Cyclin E *****
• Cyclin A
• CDK1

Question 25

What happens to Rb in HPV infection?

Answer 25

HPV produces E7 protein that binds to and inactivates Rb, so E2F can allow cell cycle to move forward

Question 26

What negatively regulates the CyclinD/CDK4-6 complex?

Answer 26

INK4 (Inhibitor of Kinase 4) a-d

Question 27

Which genes code for INK4 a-d?

Answer 27

- p16 - INK4a ******** - p15 - INK4b - p18 - INK4c - p19 - INK4d

Question 28

What positively regulates the CyclinD/CDK4-6 complex?

Answer 28

- Growth factor - MAPK - Myc oncogene - P13K/AKT

Question 29

What are the INK4 genes?

Answer 29

Tumour suppressor genes

Question 30

What negatively regulates CyclinE/CDK2 complexes?

Answer 30

CDK-Interacting Protein/Kinase Inhibitor Protein: - p12 -> CIP1 - p27 -> KIP1 - p57 -> KIP2

Question 31

What % of pancreatic cancer patients have an INK4a loss?

Answer 31

80%

Question 32

What % of T cell cancer patients have an INK4a loss?

Answer 32

75%

Question 33

What % of small cell lung cancer patients have an INK4a loss?

Answer 33

15%

Question 34

What % of breast cancer patients have an Cyclin D1 over-expression?

Answer 34

More than 50%

Question 35

What % of small cell lung cancer patients have an RB loss?

Answer 35

80%

Question 36

What point of mitosis is the point of no return?

Answer 36

Metaphase

Question 37

What complex is essential for M phase progression as far as metaphase?

Answer 37

CyclinB/CDK1

Question 38

What does CDK1 do?

Answer 38

Phosphorylates substrates involved in nuclear envelop breakdown, chromosome condensation, mitotic spindle assembly.

Question 39

What inactivates Cyclin B/CDK1?

Answer 39

When CDK1 is phosphorylated by WEE1

Question 40

What can WEE1 be activated by?

Answer 40

CHK1 (kinase)

Question 41

What is CHK1?

Answer 41

Checkpoint Kinase 1

Question 42

What do CHK1 and CHK2 also do?

Answer 42

Also phosphorylates CDC25

Question 43

What activates CHK1 and 2?

Answer 43

DNA damage detected at the G2 checkpoint

Question 44

What does dephosphorylation of Cyclin B/CDK1 by CDC25 achieve?

Answer 44

Cyclin B/CDK1 activation -> mitosis

Question 45

What is the spindle assembly checkpoint?

Answer 45

Quality control checkpoint between metaphase and anaphase

Question 46

When is mitosis allowed to progress from metaphase?

Answer 46

Only if the chromosomes are properly attached to the spindle apparatus -> GO signal.

Question 47

What does SAC promote when it gets the GO signal?

Answer 47

Degradation of cyclin B and mitosis can progress

Question 48

What promotes Cyclin B1 and Securin degradation?

Answer 48

E3 ubiquitin ligase

Question 49

What does securin do?

Answer 49

Inhibits separase enzyme that separates sister chromatids

Question 50

What is E3 ubiquitin ligase?

Answer 50

The anaphase promoting complex (APC/C)

Question 51

What happens if SAC is defective?

Answer 51

Aneuploidy

Question 52

What is aneuploidy and how common is it in cancer?

Answer 52

Gain or loss of entire chromosomes, or multiplication of the entire genome. Very common in cancer.

Question 53

Are all CDKs involved in cell cycle regulation?

Answer 53

No

Question 54

Do broad spectrum CDK inhibitors work in vivo?

Answer 54

No - probably dependant on toxicity-limited dosage

Question 55

What have CDK4-6 selective inhibitors been approved for?

Answer 55

Treatment of post-menopausal women with HR-positive, HER-2 negative advanced or metastatic cancer.

Question 56

What are the CDK4-6 selective inhibitors?

Answer 56

Palbociclib | Ribociclib