L7 - p53 and cancer Flashcards
What is p53?
It is an unusual tumour suppressor gene that is mutated in most cancers
Are people heterozygous for p53 more or less likely to get cancer?
More likely
What is confirmation specificity?
It is when an ab only recognises a protein in a specific confirmation. In the case of p53, when it is mutated it undergoes a cc and can only be recognised by certain abs
Why is it important that p53 has tetrameric structure?
If 1 su of the 4 is not functional then the protein won’t work. This explains why if you have an exogenous mutant p53 and 2 copies of the endogenous p53 you will still see a mutant phenotype
What factors upregulate p53 expression?
Lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia, blockage of transcription
What are the target genes of p53?
p53 upregulates expression of genes that block entry into cell cycle to allow DNA repair or apoptosis if necessary
What keeps p53 levels low?
Short half life and MDM2
What is the role of MDM2?
It is a ubiq ligase that tags p53 for destruction in the proteaosome. p53 also reg the levels of trsc MDM2, high levels of p53 = increased trsc of MDM2
What keeps p53 levels high?
Arf - binds MDM2 and sequesters it in the nucleolus
What effects do genotoxic stress have on p53 levels?
Increase in p53 levels due to the activation of ATM/ATR which phos p53 - active form
What happens when p53 is inact in cancer cells?
- oncogene activation without apoptosis
- higher tolerance to anoxia
- sloppy oversight of chr. integrity
What activates ATM?
Double stranded breaks
What activates ATR?
Issues with DNA replication - when DNA replication fork is affected
How can p53 reactivation be used?
Mutant p53 have an altered shape
Can screen for drugs that bind and alter p53 shape
Confirmation specific antibodies to check if drugs have altered the p53 shape
e.g. PRIMA 1
- increased number of cells in G2 - DNA repairing
- increased number of cells below G1 - this is the apoptotic population
