Cell Cycle

Question 1

Which CDK-Cyclin complexes control passage through the restriction point?

Answer 1

Cdk4-Cyclin D and CDK6-Cyclin D

Question 2

Which CDC cyclin complex controls entry into s phase

Answer 2

Cdk2-cyclin e

Question 3

Which CDK cyclin complex controls passage through a phase?

Answer 3

Cdk2 cyclin a

Question 4

Which cdk cyclin complexes control entry into mitosis?

Answer 4

Cdk1 cyclin a

Cdk1 cyclin B

Question 5

Give some. DK inhibitor proteins

Answer 5

P16
P21
P27

Question 6

How do growth factors affect cycling and CKIs?

Answer 6

Inhibit production of CKIs (cdk inhibitor proteins)

Promote production of cyclin d

Question 7

How can cancer cells avoid apoptosis?

Answer 7

Upregulate anti apoptotic pathways

Downregulate apoptotic pathways

Question 8

Give examples of down regulation of apoptotic pathways exploited by cancers

Answer 8

Loss of LKB1 pro apoptotic signal
Checkpoint defect CHK2
Mutations of DNA damage sensing system (eg p53)

Question 9

Give examples of upregulation of anti apoptotic pathways exploited in cancer

Answer 9

Pro-survival signals eg BCL-2
Loss of sensitivity to apoptotic signalling eg decoy receptors
Oncogene activation eg ras

Question 10

Give an example of a decoy receptor

Answer 10

Proteins which mimic TRAIL1 or 2 but lack functional activity

Question 11

What does LKB1 do?

Answer 11

Signals low O2 or glucose
Inhibits mTOR
Prevents mTOR mediated cell growth/proliferation, angiogenesis, cell survival

Question 12

Which cancer syndrome is as a result of mTOR overactivation?

Answer 12

Peutz-Jeghers syndrome
Many polyps in the GIT
Benign polyps but can become cancerous

Question 13

What is MDM2?

Answer 13

P53 inhibitor

Question 14

How are mdm2 and p53 regulated?

Answer 14

Inhibit each other
Mdm2 activates p53 export from nucleus
Mdm2 ubiquinates p53

Question 15

How is mdm2 regulated

Answer 15

Arf aka p14 inhibits mdm2

Question 16

Give examples of p53 actions

Answer 16

Activates death receptors; DR5 aka TRAIL2; Fas
Activates; Apaf-1; PUMA; NOXA; Bax
Inhibits Bcl-2

Question 17

How do tumour cells avoid p53?

Answer 17

Mutations in initial signalling kinases eg ATM, ATR, CHK1, CHK2
Mutations of p53
Mdm2 over expression
Arf mutations

Question 18

What is c-flip?

Answer 18

Caspase-like protein.
Shares same DED1 DED2 (death effector domains)
Lacks a cysteine residue at its binding site
So can bind death receptors but can’t continue the signal
Example of decoy receptor

Question 19

How do cancers resist TRAIL? Via decoys?

Answer 19

Expression of TRAIL receptors 3, 4 and 5 which lack the death domain
Aka (DcR1, DcR2 and osteoprotegerin respectively)
Compete with genuine TRAIL receptors 1 and 2 to antagonise apoptotic signalling

Question 20

List the methods of TRAIL signal evasion in cancer

Answer 20

Epigenetic silencing
Receptor gene mutation
Upregulation of decoy receptors (needs more evidence)
Increased c-flip activation

Question 21

What does ras do?

Answer 21

Activates raf
Activated by a GEF
Activates the MAPK pathway

Question 22

How is ras mutated in cancer?

Answer 22

Mutated to become constituently active
Codon twelve glycine for valine
Affects ability to hydrolyse GTP to GDP

Question 23

What key pathways does ras activate?

Answer 23

MEKK
raf
PI3K

Question 24

What does BAD do?

Answer 24

When unphosphorylated, is pro-apoptotic
When phosphorylated (by Akt) binds to a 1433 scaffold protein and translocates to mitochondrial membrane. Can't activate apoptosis here.

Question 25

How is PKB/Akt activated?

Answer 25

PDF- phosphorylated at threonine 308

Mtorc1 phosphorylates at serine 473