17th Feb - The CDK2A locus, p21 and PTEN

Question 1

What is the role of p16INK4?

Answer 1

To inhibit the Rb pathway, therefore inhibit Cyclin D-CDK4/6 thus cause G1 arrest

Question 2

Outline the mechanism of p16INK4’s function

Answer 2

p16 –| Cyclin D- CDK 4/6 therefore inhibiting RB phosphorylation causing it to release E2F and thus inhibiting cell division

Question 3

Where was p16INK4 first discovered in 1993?

Answer 3

As a melanoma susceptibility gene on chromosome 9p21

Question 4

How is p16INK4 suppressed in many tumours?

Answer 4

promoter methylation

Question 5

What is the biomarker for senescence?

Answer 5

p16INK4

Question 6

Where is p6INK4 encoded?

Answer 6

On the CDKN2A locus

Question 7

What is the function of p21?

Answer 7

To cause cell cycle arrest

Question 8

Outline the overall function of the CIP/KIP family

Answer 8

p57KIP2
p27KIP1
p21CIP1

inhibit

Cyclin E- CDK2
Cyclin A - CDK2

causing

Cell cycle arrest

Question 9

What induces p21 production?

Answer 9

DNA damage
Oxidative stress
Cyclokines and mitogens
Tumour viruses
Anticancer agents
p53

Question 10

What is the action of p21?

Answer 10

It inhibits proliferating cell nuclear antigen (PCNA) thus inhibiting DNA repair

It inhibits CDK2 thus inhibiting gene transcription and promoting cell cycle arrest, differentiation and senescence

It also inhibits apoptosis and gene transcription directly

Question 11

Is p21 a tumour suppressor?

Answer 11

It stops cell proliferation and induces senescence and can induce apoptosis

BUT

it normally prevents apoptosis and may promote oncogenes and it is rarely mutated in cancer

Question 12

Outline the moderate stress pathway of p53 for p21

Answer 12

p53 –> p21 –> CDK5 –> cell cycle arrest

p53–> p21 –> NRF2 –> decreased ROS, apoptosis, and other stress

Question 13

Outline the high stress pathway of p53 for p21

Answer 13

p53 –> p21 –> cell cycle arrest

Question 14

?What are the products of the CDK2A locus

Answer 14

p16 and p14 (ARF)

Question 15

What is the main function of p14ARF?

Answer 15

To inhibit MDM2 by sequestering it in the nucleolus therefore preventing p53 ubiquitination

Question 16

When is p14ARF mainly induced?

Answer 16

After sustained oncogenic stress

Question 17

Outline the mechanism of p14ARF

Answer 17

E1A/c-Myc/Ras –> E2F –> ARF –| MDM2 –| p53 –> cell cycle arrest and apoptosis

Question 18

Give an example of ARF suppression in cancer

Answer 18

Pokemon suppresses ARF in breast, lung, colon and bladder cancer

Question 19

What is PTEN?

Answer 19

A tumour suppressor with phosphatase activity

Question 20

What is the function of PTEN?

Answer 20

Dephosphorylates PIP3 thus opposing PI3K and blocking cell proliferation

Question 21

How is PTEN commonly regulated in cancer?

Answer 21

It is commonly downregulated for example in prostate, lung and brain cancer

Question 22

How is PTEN activated?

Answer 22

It can be induced by p53

Question 23

What is the role of PTEN in p53 regulation?

Answer 23

Believed to be part of p53’s modulation i.e. determining whether p53 promotes apoptosis or senescence

p53 + PTEN –> apoptosis
p53 w/o PTEN –> senescence

Question 24

How does PTEN promote p53 to induce apoptosis?

Answer 24

PTEN inhibits PKB thus preventing it from inhibiting caspases, inducing apoptosis

Question 25

What would be the main advantage of re-activating tumour suppressors rather than inhibiting oncogenes, therapeutically?

Answer 25

Reactivating a tumour suppressor means that we would only need 1 drug, where as inhibiting an oncogene requires many drugs