L7. Regulation Of CC Flashcards
How is CDK activated
Cyclin binds to cdk = partially active
A phosphorylation event catalysed by CDK activating kinase (CAK) fully activates it
How is the cdk cyclin complex inactived
A 2nd phosphorylation event inhibits the CdK complex
Catalysed by wee1kinase
How can the cyclin cdk complex be reactivated after wee1kinase
Cdc25 phosphatase remibes the Second phosppphat group
Give 3 examples of cyclin cdk inhibitors
P27
P21
P16
What effect does p27 have
Suppresses g1/s ans cdk-S activity in G1
Cell can withdraw from the cell cycle
Cell can’t pass through the R point
What effect does p21 have
Activates if dna damage is detected
Suppresses g1/s ans cdk-S activity in G1
Cell can’t pass through R point
What effect does p16 have
Suppresses g1/s ans cdk-S activity in G1
Inactivated in cancer cells
Can’t pass through R point
How are cyclins degraded
Ubiquitin mediated degradation
Explain ubiquitin degradation of cyclins
Cyclins contain a.a that are recognised by ubiquitin
Ubiquitin tags the cyclins for degradation by the proteosome
What cyclins contain destruction boxes
A and B
What cyclins contain PEST sequences
D and E
What are PEST sequences
Rich in proline, glutamic acid, serine and threonine
These sequences are recognised by enzymes which add ubiquitin to them
Flagging for degradation by the proteosome
Explain the ubiquitination of M phase cyclin complex
The cyclin cdk complex is Cyclin B cdk 1
- The anaphase promoting complex (APC) is activated by the activating sub unit cdc20
- The APC can then add ubiquitin to the cyclin B
What Is responsible for adding ubiquitin in the G1/S phase
SFC ubiquitin ligase complex
What Is responsible for adding ubiquitin in the M phase
Anaphase promoting sequence
What is the R checkpoint
Standard control braking system
Allows the cell to stop and check for favourable conditions or dna damage
If the cell doesn’t get the signal to go through the R point it can stay in G1, go into G0 or enter apoptosis
Describe the regulation of the G1 checkpoint
Rb + E2F = E2F inactive = S phase genes are switched off = can’t pass through G1 checkpoint
If cyclin D/cdk 4 phosphorylates Rb = E2F is released = S phase genes switched on = can pass through G1
CDK inhibitors can bind to cyclin D/cdk 4 = sto phosphorylation of Rb = E2F rebound to Rb = cell can’t pass through G1
How do cancer cells get passed the G1 checkpoint if their dna is damaged
- Mutate Rb gene so that E2F is always active
- Increase levels of cyclin D so that cdk 4 is always active = E2F is always being phosphorylated = S phase genes always switched on
- Loss of cdk inhibitors = E2F constantly phosphorylated
How do cells stop progress through the cell cycle if there is dna damage
- Damage sensed by protein kinase
- P53 is phosphorylated
- Mdm2 is removed
- P53 is stable and active
- P53 is a transcription factor and targets p21
- P21 synthesis increases
- P21 binds to active cyclin cdk complex
Stop cc progress
How is progression through the cc restarted
P53 levels are very low in normal cells
P53 associated with mdm2
P53 gets tagged by ubiquitin
Contantly degraded by the proteosome
What happens if dna damage cannot be repaired
P21 activates apoptosis
How does the gf mitogen help the cell progress through the g1 checkpoint
- Mitogen binds to cell surface receptor
- Receptor activated
- Sets of cascade of intracellular-signalling
- Cyclin D syntheised
- Activates cyclin D/CdK 4 complex
- Phosphorylates Rb
- E2F released
- S phase genes switched on
Give an example of an inhibitory gf
TGF beta
What does TGF beta do
Switches on synthesis for cyclin dependant kinase inhibitor proteins
Eg. P16 and P21
