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Biology of Cancer SSC > Cell Cycle Control > Flashcards

Cell Cycle Control Flashcards

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1
Q

What are the phases of the cell cycle?

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

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

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2
Q

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

A

Cyclin Dependant Kinases (CDKs)

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3
Q

What are CDKs?

A

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

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4
Q

What do CDK substrates do?

A

Promote cell cycle progression

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5
Q

When are CDKs only active?

A

When they are bound to their partner cyclins

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6
Q

How do CDK levels change during cell cycle?

A

They are relatively stable

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7
Q

How do cyclin levels change during cell cycle?

A

They rise and fall to cause oscillation in CDK activation

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8
Q

Which CDKs operate during G1?

A

CDK4-6

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9
Q

Which Cyclins operate with CDK4-6?

A

Cycin D1, D2 and D3

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10
Q

Which CDK operates during G1/S?

A

CDK2

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11
Q

Which CDK operates during S phase?

A

CDK2

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12
Q

Which CDK operates during Mitosis?

A

CDK1

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13
Q

Which cyclins operate with CDK2 in G1/S?

A

Cyclin E1 and E2

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14
Q

Which cyclins operate with CDK2 in S phase?

A

Cyclins A1 and A2

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15
Q

Which cyclin operates with CDK1 in Mitosis?

A

Cyclin B1

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16
Q

Which complex is essential for entry into G1?

A

CyclinD/CDK4-6

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17
Q

What complexes regulate G1 to S progression?

A

CyclinE/CDK2

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18
Q

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

A

Trigger DNA polymerase action

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19
Q

What complex promotes entry into Mitosis?

A

CyclinA/CDK1

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20
Q

What does the retinoblastoma protein normally do?

A

Inhibits progression through the cell cycle by inhibiting E2F transcription factor

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21
Q

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

A

CyclinD/CDK4-6

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22
Q

Which complex also phosphorylates Rb to completely inactivate it?

A

CyclinE/CDK2

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23
Q

What does this complete phosphorylation of Rb result in?

A

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

24
Q

What S-phase genes are pushed through by E2F?

A
  • DNA synthesis
  • DNA replication
  • DNA repair
  • Cyclin E *****
  • Cyclin A
  • CDK1
25
Q

What happens to Rb in HPV infection?

A

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

26
Q

What negatively regulates the CyclinD/CDK4-6 complex?

A

INK4 (Inhibitor of Kinase 4) a-d

27
Q

Which genes code for INK4 a-d?

A
  • p16 - INK4a **
  • p15 - INK4b
  • p18 - INK4c
  • p19 - INK4d
28
Q

What positively regulates the CyclinD/CDK4-6 complex?

A
  • Growth factor
  • MAPK
  • Myc oncogene
  • P13K/AKT
29
Q

What are the INK4 genes?

A

Tumour suppressor genes

30
Q

What negatively regulates CyclinE/CDK2 complexes?

A

CDK-Interacting Protein/Kinase Inhibitor Protein:

  • p12 -> CIP1
  • p27 -> KIP1
  • p57 -> KIP2
31
Q

What % of pancreatic cancer patients have an INK4a loss?

A

80%

32
Q

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

A

75%

33
Q

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

A

15%

34
Q

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

A

More than 50%

35
Q

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

A

80%

36
Q

What point of mitosis is the point of no return?

A

Metaphase

37
Q

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

A

CyclinB/CDK1

38
Q

What does CDK1 do?

A

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

39
Q

What inactivates Cyclin B/CDK1?

A

When CDK1 is phosphorylated by WEE1

40
Q

What can WEE1 be activated by?

A

CHK1 (kinase)

41
Q

What is CHK1?

A

Checkpoint Kinase 1

42
Q

What do CHK1 and CHK2 also do?

A

Also phosphorylates CDC25

43
Q

What activates CHK1 and 2?

A

DNA damage detected at the G2 checkpoint

44
Q

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

A

Cyclin B/CDK1 activation -> mitosis

45
Q

What is the spindle assembly checkpoint?

A

Quality control checkpoint between metaphase and anaphase

46
Q

When is mitosis allowed to progress from metaphase?

A

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

47
Q

What does SAC promote when it gets the GO signal?

A

Degradation of cyclin B and mitosis can progress

48
Q

What promotes Cyclin B1 and Securin degradation?

A

E3 ubiquitin ligase

49
Q

What does securin do?

A

Inhibits separase enzyme that separates sister chromatids

50
Q

What is E3 ubiquitin ligase?

A

The anaphase promoting complex (APC/C)

51
Q

What happens if SAC is defective?

A

Aneuploidy

52
Q

What is aneuploidy and how common is it in cancer?

A

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

53
Q

Are all CDKs involved in cell cycle regulation?

A

No

54
Q

Do broad spectrum CDK inhibitors work in vivo?

A

No - probably dependant on toxicity-limited dosage

55
Q

What have CDK4-6 selective inhibitors been approved for?

A

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

56
Q

What are the CDK4-6 selective inhibitors?

A

Palbociclib

Ribociclib

Biology of Cancer SSC (16 decks)

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