17th Feb - The CDK2A locus, p21 and PTEN Flashcards
What is the role of p16INK4?
To inhibit the Rb pathway, therefore inhibit Cyclin D-CDK4/6 thus cause G1 arrest
Outline the mechanism of p16INK4’s function
p16 –| Cyclin D- CDK 4/6 therefore inhibiting RB phosphorylation causing it to release E2F and thus inhibiting cell division
Where was p16INK4 first discovered in 1993?
As a melanoma susceptibility gene on chromosome 9p21
How is p16INK4 suppressed in many tumours?
promoter methylation
What is the biomarker for senescence?
p16INK4
Where is p6INK4 encoded?
On the CDKN2A locus
What is the function of p21?
To cause cell cycle arrest
Outline the overall function of the CIP/KIP family
p57KIP2
p27KIP1
p21CIP1
inhibit
Cyclin E- CDK2
Cyclin A - CDK2
causing
Cell cycle arrest
What induces p21 production?
DNA damage Oxidative stress Cyclokines and mitogens Tumour viruses Anticancer agents p53
What is the action of p21?
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
Is p21 a tumour suppressor?
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
Outline the moderate stress pathway of p53 for p21
p53 –> p21 –> CDK5 –> cell cycle arrest
p53–> p21 –> NRF2 –> decreased ROS, apoptosis, and other stress
Outline the high stress pathway of p53 for p21
p53 –> p21 –> cell cycle arrest
?What are the products of the CDK2A locus
p16 and p14 (ARF)
What is the main function of p14ARF?
To inhibit MDM2 by sequestering it in the nucleolus therefore preventing p53 ubiquitination
When is p14ARF mainly induced?
After sustained oncogenic stress
Outline the mechanism of p14ARF
E1A/c-Myc/Ras –> E2F –> ARF –| MDM2 –| p53 –> cell cycle arrest and apoptosis
Give an example of ARF suppression in cancer
Pokemon suppresses ARF in breast, lung, colon and bladder cancer
What is PTEN?
A tumour suppressor with phosphatase activity
What is the function of PTEN?
Dephosphorylates PIP3 thus opposing PI3K and blocking cell proliferation
How is PTEN commonly regulated in cancer?
It is commonly downregulated for example in prostate, lung and brain cancer
How is PTEN activated?
It can be induced by p53
What is the role of PTEN in p53 regulation?
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
How does PTEN promote p53 to induce apoptosis?
PTEN inhibits PKB thus preventing it from inhibiting caspases, inducing apoptosis
What would be the main advantage of re-activating tumour suppressors rather than inhibiting oncogenes, therapeutically?
Reactivating a tumour suppressor means that we would only need 1 drug, where as inhibiting an oncogene requires many drugs
