Genomes-L7-Tumour Suppressor genes: P53

what does P53 do?

a tumour supressor gene

• It is a TF that is involved in responding to DNA damage

• it can stop cell division or promote apoptosis

does this by turning on genes that stop cell cycle or apoptosis such as Not Puma, Bad

what was P53 discovered?

monkey virus-SV40- tumours due to large tumour

• encodes protein that can neutralise function of pRB and P53

i

nfecting mice with SV40- immune response against large T antigen

• large T antigen was studied through gel electrophoresis- p53- involved in development of cancer(usually suppresses transformation)

P53- what does it usually do - what type of mutation occurs?

• usually suppresses proliferation in response to DNA damage

• a single mutant- usually missense mutations

P53 function and stability- how does it work, life time and what genes does it help express?

1. P53 is a tetramer-a single mutant disrupts the rest of them

2. P53 has a short half life- due to Mdm2

3. P53 triggers expression of genes that trigger apoptosis by Bax, Noxa, Puma

what does P53 have a short half life

stability of P53 is controlled by Hmd2 in human cells

• Mdm2 binds to p53- targets protein for degradation via ubiquitin proteasome

• Mdm2 exports p53 out nucleus too- stops it from binding to DNA and stops TF activity

what happens with p53 degradation

Mdm2 is degraded- by phosphorylation of ATM kinase which detects DNA strand breaks

• Mdm2 also is phosphorylated by CHK1 and Chk2- checkpoint 1 and 2

where are P53 mutations usually found?

• found in the DNA binding domain of the protein

• this creates p53 mutant that can form the tetramer but cannot bind t target genes in the DNA- making a dominant interfering mutant protein- neutralise the function of normal p53

• p53 controls expression of inhibitor Mdm2

difference between passenger and driver mutations

• Passenger mutations are random changes in the genome that do not influence cancer progression

• driver mutations are crucial for tumor development and give the cancer cell a growth advantage.

examples of actionable genes

KRAS, EGFR, BRAC1, BRAC2