L11 - The Cell Cycle II Flashcards
What cyclins and CDKs are found after the R point?
E-type cyclins associate with CDK2 –> phosphorylation of substrates required for entry into S phase
What cyclins and CDKs are found during G1?
CDK4 and CDK6 depend on the association with D type cyclins
What cyclins and CDKs are found during S phase?
A-type cyclins replace E cyclins in complex with CDK2 –> S phase progression
Later, A-type cyclins associate with CDC2 (CDK1)
What cyclins and CDKs are found during G2?
B-type cyclins replace A-type cyclins in the complex with CDC2
What cyclins and CDKs are found during M phase?
B-type cyclins/CDC2 mitosis triggering
What cyclins and CDKs are found during Go-G1?
Mediated by cyclin C/CDK3 complex
How do cyclin Es level change during the cell cycle?
Low levels throughout G1, rapid increase after the R point
How do cyclin As level change during the cell cycle?
Levels increase in concert with the entrance in S phase
How do cyclin Bs level change during the cell cycle?
Levels increase in anticipation of mitosis
What drops in levels are the cell progresses through the cell cycle?
Cyclin levels
Degradation is ubiquitination-dependent
Cell cycle can only progress in one direction
What cyclin does not change its level during the cell cycle?
D-type
What are D-type cyclins controlled by?
Controlled by extracellular signals - growth factors and integrin-mediated ECM attachment
Removal of growth factor leads to rapid collapse of cyclin D1 levels
What is the role of D-type cyclins?
They covey messages from extracellular environment to cell cycle clock in the nucleus
- Part of critical time point in G1 where the cell communicates with extracellular environment
Synthesised in the cytoplasm and transported in the nucleus
What are other cyclins controlled by?
Regulated by intracellular signals and coordinated with cell cycle advance
What is the role of cyclin/CDKs?
Activate complexes of the subsequent phase
Inhibit complexes active in the previous phase
What are cyclin/CDKs regulated by?
CDK inhibitors
CDK inhibitor family
Family of 7 proteins antagonising the activity of cyclin/CDKs
Divided into 2 groups
- 4 PINK proteins – inhibit D-CDK4/6 complex
- 3 PKIP/CIP proteins – inhibit the E-CDK2, A-CDK2, A-CDC2, B-CDC2 complexes
How does TGFb control cell cycle progression?
TGF-b inhibits cell cycle progression via induction of CDKI
How does TGFb signalling play a role in pathogenesis of carcinomas?
Early stages - arrests the growth of many cell types
Later stages - contributes to tumour invasiveness
What is the TGFb signalling pathway involved in?
Cell growth
Cell differentiation
Apoptosis
TGFb ligand binding pathway
TGFb superfamily ligands bind to a type II receptor
This recruits and phosphorylates a type I receptor
Type I receptor then phosphorylates receptor-regulated SMADs
Can now bind the coSMAD SMAD4
R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in regulation of target gene expression
TGFb increases the levels of?
p15INK4B
Leads to inhibition of cyclin D-CDK4/6 complexes
Cells can’t reach the R point
TGFb weakly increases the levels of?
p21Cip1
Stronger induction upon DNA damage
Cell cycle is halted until the genome is repaired
How do extracellular signals control cell cycle progression?
Mitogens promote cell cycle progression via inhibition of CDKI
Akt phosphorylated what in the nucleus?
p21Cip1
Translocation of p21 to cytoplasm
Akt phosphorylated what in the cytosol?
p27Kip1
Prevents translocation of p27 to nucleus
Correlates with poor prognosis in breast cancer
What is the importance of Akt activation keeping the CDKI in the cytoplasm?
They cannot inhibit the CDK complexes which are kept in the nucleus
What is easier to identify in strong cancers?
Active phosphorylated Akt
P27 in nucleus and cytoplasm – worse survival rate
What is active Akt used for?
Used to identify which types of tumours are likely to progress and become more aggressive
Kaplan Meis survival curve – non parametric statistical method used to estimate the survival function
