The cell cycle II Flashcards
What cyclin/CDK pairs controls G1?
Association of D-type cyclins (D1, D2 or D3) with CDK4 and CDK6
What cyclin/CDK pairs controls G1 after the R point?
E-type cyclins (E1 and E2) with CDK2
What does cyclin E/CDK2 mediate?
The phosphorylation of substrates required for ENTRY into the S phase
What cyclin/CDK pairs controls the beginning of S phase?
What mediates S phase later on?
A-type cyclins (A1 and A2) replace cyclin E in complex with CDK2
Cyclin A/Cdc2 later on in S phase
What is Cdc2 also known as?
CDK1
What cyclin/CDK pairs controls G2?
B-type cyclings with Cdc2 (CDK1)
What does cyclin B/Cdc2 trigger?
Mitosis
What is the G0 –> G1 transition mediated by?
Cyclin C/CDK3 complex
Describe the levels of cyclin E in G1
Low during most of G1
Rapid increase after the R point
When do cyclin A levels increase?
In concert with entrance to the S phase
What happens to cyclin B levels in the cell cycle?
Increases with anticipation into mitosis
Levels drop once mitosis has finished
How do cycling levels decrease?
Degradation of the protein by ubiquitination
What ensures that the cell cycle only occurs in one direction?
What is the exception to this?
Cyclins GRADUALLY accumulate and are RAPIDLY degraded
Cyclin D is the exception - levels don’t change during the cell cycle
How is cyclin D regulated?
By EXTRACELLULAR signals:
1) Growth factors
2) Integrin-mediated ECM attachment
What is the function of cyclin D?
To convey messages from the EXTRACELLULAR environment to the CELL CYCLE CLOCK
Where is the cell cycle clock present?
In the NUCLEUS
How does cyclin D achieve its function?
Cyclin D is synthesised in the cytoplasm and transported to the nucleus (where the cell cycle clock is present)
ONLY when the environment is right to undergo CELL PROLIFERATION
How does cyclin D fluctuate?
NUCLEAR cyclin D fluctuates (but the amount of cyclin D in the cell doesn’t)
What occurs in G1, before the R point?
Cells asses their environment and decide if the environment is right to divide or not
What is the decision to divide or not in G1 taken by?
Controlling the activity of cyclin D
What happens is cyclin D goes into the nucleus in G1?
It associates with CDK4/6 and triggers the cells THROUGH the R point
What happens if cyclin D is not localised in the nucleus in G1?
When might this happen?
Cell cycle cannot proceed
In the ABSENCE of GF
When the cell is not attached to the ECM
What is the only cyclin that is regulated by extracellular signals?
Cyclin D
What are the cyclins NOT dependant on after the R point?
What are they dependant on instead?
NOT dependant on extracellular signals
Dependant on autonomous, intracellulr signals
What do cyclin/CDKs activate?
Inhibit?
What does this ensure?
Active the formation of the complexes in the subsequent phases
Inhibit the complexes in the previous phase
Ensures that the cell cycle only occurs in 1 direction
What activates cyclin A?
What does cyclin A do following this activation?
Activated during the G1/S phase by cyclin E/CDK2
Replaces cyclin E in the complex and leads to the inactivation of cyclin E
Cyclin A-CDK2 complex then ACTIVATES the cyclin B/Cdc2, which inactivates the synthesis of cyclin A
What are CKIs?
CKD inhibitors
How many CKIs are there?
7
What are the 2 groups of CKIs?
What are the members of these groups?
1) CKIs that inhibit the cyclin D/CDK4/6 complex but has NO activity towards the other complexes
(4 x INK4 proteins)
2) CKIs that inhibit the other cyclin/CDK complexes (E,A, B) but has no activity towards cyclin D
(P57^Kip2, P27^Kip1 P21^Cip1)
What does TGFb play a role in?
How?
The pathogenesis of many carcinomas
Plays a different role in the different stages of cancer:
Early stages - Arrests the growth of many cell types
Late stages - Contributes to tumour invasivness and metastasis
What does TGFb control?
- Cell growth
- Cell differentiation
- Apoptosis
- Cellular homeostasis
What is the process of TGFb superfamily signalling?
1) Ligand binds type II receptors
2) Recruits type I receptor which DIMERISES and activates type II
3) Type II phosphorylates type I and leads to the overall activation of the receptor
4) Activated receptor phosphorylates specifics receptor-regulated SMAD proteins (r-SMADs) , which recruits SMAD4 (coSMAD) to form a complex
5) This complex acts as a TF and translocates into the nucleus to regulate gene expression
What are the genes that are controlled by the R-SMAD/coSMAD complex?
What does this cause?
CDI:
- Strongly INCREASES levels of P15^INK4B
- Causes the inhibition of cyclinD/CDK4/6
- Cells don’t reach the R point
- Cells don’t proliferate
- Weakly induces p21^Cip1
When is P21^Cip1 more strongly induced by TGFb signalling?
What does this cause? Why?
Upon DNA damage
Inhibition of most cyclin/CDK complexes - to HALT the cell cycle whilst repair takes place
How do GF/mitogenic factors promote the advancement of the cell cycle?
Process?
They MUTE the action of CKI:
- Bind to the receptors
- Activate the P13 pathway
- Leads to the activation of Akt (PKB)
1) Akt/PKB phosphorylates p21^Cip in the NUCLEUS, causing its translocation to the cytoplasm
2) Akt/PKB phosphoylates p27^Kip in the CYTOSOL, PREVENTING the translocation to the nucleus
- p27 and p21 cannot function in the cytosol - cyclin-CDK complexes can trigger the progression of the cell cycle (not blocked)
How can the effect of Akt/PKB be seen in the cell?
When they are stained with an antibody marker
What is seen in constitutively active Akt/PKB?
Most p21^Cip is in the cytosol
No blockage of cyclin-CKD complexes
What is seen in dominant-negative Akt/PKB?
Most p21^Cip in in the nucleus
Blocks cyclin-CDK complexes
What is the difference between patients that have breast cancer that have P27^Kip in the nucleus or in BOTH the nucleus and the cytoplasm?
In the nucleus - Higher survival rate
In the nucleus and the cytoplasm - Lower survival rate
In patients with breast cancer, what does Akt activation correlate with?
Cytoplasmic p27^Kip
No blockage of cell growth
What can the localisation of p27^Kip be used as?
BUT, what doesnt this mean?
A prognostic marker to identify which kind or tumours are more likely to progress and become more aggressive
DOESN’T mean that cytoplasmic p27^Kip causes breast cancer
