Cell Cycle Control Flashcards
What are the phases of the cell cycle?
- M (mitosis)
- G1 (preparation for DNA replication)
- S (DNA synthesis)
- G2 (preparation for mitosis)
Also G0 (non-proliferating/quiescent cells sit here)
What are the key regulators of transition between cell cycle phases?
Cyclin Dependant Kinases (CDKs)
What are CDKs?
Serine/Theonine kinases - phosphorylate substrates at certain motifs contaning these
What do CDK substrates do?
Promote cell cycle progression
When are CDKs only active?
When they are bound to their partner cyclins
How do CDK levels change during cell cycle?
They are relatively stable
How do cyclin levels change during cell cycle?
They rise and fall to cause oscillation in CDK activation
Which CDKs operate during G1?
CDK4-6
Which Cyclins operate with CDK4-6?
Cycin D1, D2 and D3
Which CDK operates during G1/S?
CDK2
Which CDK operates during S phase?
CDK2
Which CDK operates during Mitosis?
CDK1
Which cyclins operate with CDK2 in G1/S?
Cyclin E1 and E2
Which cyclins operate with CDK2 in S phase?
Cyclins A1 and A2
Which cyclin operates with CDK1 in Mitosis?
Cyclin B1
Which complex is essential for entry into G1?
CyclinD/CDK4-6
What complexes regulate G1 to S progression?
CyclinE/CDK2
What do CyclinA/CDK2 complexes do during S and G2?
Trigger DNA polymerase action
What complex promotes entry into Mitosis?
CyclinA/CDK1
What does the retinoblastoma protein normally do?
Inhibits progression through the cell cycle by inhibiting E2F transcription factor
What initially phosphorylates Rb protein into its inactive form so that Cyclin E can be transcribed?
CyclinD/CDK4-6
Which complex also phosphorylates Rb to completely inactivate it?
CyclinE/CDK2
What does this complete phosphorylation of Rb result in?
E2F is not inhibited so S-Phase genes can be synthesised.
What S-phase genes are pushed through by E2F?
- DNA synthesis
- DNA replication
- DNA repair
- Cyclin E *****
- Cyclin A
- CDK1
What happens to Rb in HPV infection?
HPV produces E7 protein that binds to and inactivates Rb, so E2F can allow cell cycle to move forward
What negatively regulates the CyclinD/CDK4-6 complex?
INK4 (Inhibitor of Kinase 4) a-d
Which genes code for INK4 a-d?
- p16 - INK4a **
- p15 - INK4b
- p18 - INK4c
- p19 - INK4d
What positively regulates the CyclinD/CDK4-6 complex?
- Growth factor
- MAPK
- Myc oncogene
- P13K/AKT
What are the INK4 genes?
Tumour suppressor genes
What negatively regulates CyclinE/CDK2 complexes?
CDK-Interacting Protein/Kinase Inhibitor Protein:
- p12 -> CIP1
- p27 -> KIP1
- p57 -> KIP2
What % of pancreatic cancer patients have an INK4a loss?
80%
What % of T cell cancer patients have an INK4a loss?
75%
What % of small cell lung cancer patients have an INK4a loss?
15%
What % of breast cancer patients have an Cyclin D1 over-expression?
More than 50%
What % of small cell lung cancer patients have an RB loss?
80%
What point of mitosis is the point of no return?
Metaphase
What complex is essential for M phase progression as far as metaphase?
CyclinB/CDK1
What does CDK1 do?
Phosphorylates substrates involved in nuclear envelop breakdown, chromosome condensation, mitotic spindle assembly.
What inactivates Cyclin B/CDK1?
When CDK1 is phosphorylated by WEE1
What can WEE1 be activated by?
CHK1 (kinase)
What is CHK1?
Checkpoint Kinase 1
What do CHK1 and CHK2 also do?
Also phosphorylates CDC25
What activates CHK1 and 2?
DNA damage detected at the G2 checkpoint
What does dephosphorylation of Cyclin B/CDK1 by CDC25 achieve?
Cyclin B/CDK1 activation -> mitosis
What is the spindle assembly checkpoint?
Quality control checkpoint between metaphase and anaphase
When is mitosis allowed to progress from metaphase?
Only if the chromosomes are properly attached to the spindle apparatus -> GO signal.
What does SAC promote when it gets the GO signal?
Degradation of cyclin B and mitosis can progress
What promotes Cyclin B1 and Securin degradation?
E3 ubiquitin ligase
What does securin do?
Inhibits separase enzyme that separates sister chromatids
What is E3 ubiquitin ligase?
The anaphase promoting complex (APC/C)
What happens if SAC is defective?
Aneuploidy
What is aneuploidy and how common is it in cancer?
Gain or loss of entire chromosomes, or multiplication of the entire genome.
Very common in cancer.
Are all CDKs involved in cell cycle regulation?
No
Do broad spectrum CDK inhibitors work in vivo?
No - probably dependant on toxicity-limited dosage
What have CDK4-6 selective inhibitors been approved for?
Treatment of post-menopausal women with HR-positive, HER-2 negative advanced or metastatic cancer.
What are the CDK4-6 selective inhibitors?
Palbociclib
Ribociclib
