Tumour Suppressors II

Question 1

How do Akt and CHk1/2 phosphorylation of MDM2 differ?

Answer 1

Akt phosphorylation promotes nuclear entry and p53 association.
Chk1/2 promotes dissociation of MDM2 from p53.

Question 2

How is p21 involved in oncogenic stress induced cell cycle p53 expression?

Answer 2

p53 induces the expression of p21. p21 inhibits CDK4/6-Cyclin E complexes.
Sustained accumulation of p21 may induced premature cell senescence.
Sustained p53 may induce apoptosis.

Question 3

What parts of the p53 pathway have been shown to be defective in cancers?

Answer 3

MDM2 or MDM4 overexpression (retinoblastoma)

Inactivation of DNA damage kinases (e.g. germline mutations in Chk2 in some Li-Fraumeni families)

Defective transcriptional regulation of p53 (low p53 in breast tumours due to HOXA5 suppression).

Question 4

What do gain of function mutations target?

Answer 4

Altered target gene specificity
Switch from transcriptional repression to activation.
Promotion of chemoresistance
Selective loss of p53 transcriptional targets
Direct inhibition of signalling pathways through altered PPIs.

Question 5

What is the effect of phosphorylation on p53 activity?

Answer 5

Low levels displace MDM2
High levels –> promote recruitment of transcriptional co-activators.
Affinity of p53 for promoters of target genes vary (high for MDM2 and p21 but low for apoptotic genes)

Question 6

How does acetylation affect p53 activity?

Answer 6

Required for transcriptional activation of most p53 target genes (not MDM2!)
Specific acetylation pattern dictates p53 promoter preference. (e.g. K120 acetylation guides p53 to pro-apoptotic genes e.g. Bax and PUMA).

Question 7

Broadly speaking, what is LoH?

Answer 7

LoH at a locus = loss of 1 of 2 parental alleles at that locus.