L11 - The Cell Cycle II

Question 1

What cyclins and CDKs are found after the R point?

Answer 1

E-type cyclins associate with CDK2 –> phosphorylation of substrates required for entry into S phase

Question 2

What cyclins and CDKs are found during G1?

Answer 2

CDK4 and CDK6 depend on the association with D type cyclins

Question 3

What cyclins and CDKs are found during S phase?

Answer 3

A-type cyclins replace E cyclins in complex with CDK2 –> S phase progression
Later, A-type cyclins associate with CDC2 (CDK1)

Question 4

What cyclins and CDKs are found during G2?

Answer 4

B-type cyclins replace A-type cyclins in the complex with CDC2

Question 5

What cyclins and CDKs are found during M phase?

Answer 5

B-type cyclins/CDC2  mitosis triggering

Question 6

What cyclins and CDKs are found during Go-G1?

Answer 6

Mediated by cyclin C/CDK3 complex

Question 7

How do cyclin Es level change during the cell cycle?

Answer 7

Low levels throughout G1, rapid increase after the R point

Question 8

How do cyclin As level change during the cell cycle?

Answer 8

Levels increase in concert with the entrance in S phase

Question 9

How do cyclin Bs level change during the cell cycle?

Answer 9

Levels increase in anticipation of mitosis

Question 10

What drops in levels are the cell progresses through the cell cycle?

Answer 10

Cyclin levels
Degradation is ubiquitination-dependent
Cell cycle can only progress in one direction

Question 11

What cyclin does not change its level during the cell cycle?

Answer 11

D-type

Question 12

What are D-type cyclins controlled by?

Answer 12

Controlled by extracellular signals - growth factors and integrin-mediated ECM attachment
Removal of growth factor leads to rapid collapse of cyclin D1 levels

Question 13

What is the role of D-type cyclins?

Answer 13

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

Question 14

What are other cyclins controlled by?

Answer 14

Regulated by intracellular signals and coordinated with cell cycle advance

Question 15

What is the role of cyclin/CDKs?

Answer 15

Activate complexes of the subsequent phase

Inhibit complexes active in the previous phase

Question 16

What are cyclin/CDKs regulated by?

Answer 16

CDK inhibitors

Question 17

CDK inhibitor family

Answer 17

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

Question 18

How does TGFb control cell cycle progression?

Answer 18

TGF-b inhibits cell cycle progression via induction of CDKI

Question 19

How does TGFb signalling play a role in pathogenesis of carcinomas?

Answer 19

Early stages - arrests the growth of many cell types

Later stages - contributes to tumour invasiveness

Question 20

What is the TGFb signalling pathway involved in?

Answer 20

Cell growth
Cell differentiation
Apoptosis

Question 21

TGFb ligand binding pathway

Answer 21

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

Question 22

TGFb increases the levels of?

Answer 22

p15INK4B
Leads to inhibition of cyclin D-CDK4/6 complexes
Cells can’t reach the R point

Question 23

TGFb weakly increases the levels of?

Answer 23

p21Cip1
Stronger induction upon DNA damage
Cell cycle is halted until the genome is repaired

Question 24

How do extracellular signals control cell cycle progression?

Answer 24

Mitogens promote cell cycle progression via inhibition of CDKI

Question 25

Akt phosphorylated what in the nucleus?

Answer 25

p21Cip1

Translocation of p21 to cytoplasm

Question 26

Akt phosphorylated what in the cytosol?

Answer 26

p27Kip1
Prevents translocation of p27 to nucleus
Correlates with poor prognosis in breast cancer

Question 27

What is the importance of Akt activation keeping the CDKI in the cytoplasm?

Answer 27

They cannot inhibit the CDK complexes which are kept in the nucleus

Question 28

What is easier to identify in strong cancers?

Answer 28

Active phosphorylated Akt

P27 in nucleus and cytoplasm – worse survival rate

Question 29

What is active Akt used for?

Answer 29

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