The p53 pathway Flashcards
Describe the structure of p53
has a domain structure typical for transcription factors, with distint DNA binding and multimerisation domains
What is the most well known job of the p53
tumor supression
what are the other positive outcomes of p53 pathway
Development
stem cell modulation
fertility
What are the negative outcomes of p53 pathways
Ischemia
Treacher Collins syndrome
Neurodegeneration
Ageing
What are the developmental processes effected by p53 pathways
Apoptosis, Autophagy, Cell cycle arrest, DNA repair, Embryo implantation, inhibition of angiogenesis and ROS/survival, innate immunity, metabolsim, senescence, as well as p53 regulation
how do NF-kB, p53 and HIF interact
many functions of the 3 pathways overlap, depending on context they either function cooperatively or antagonistically to help determine the response to cell stress
What occurs to p53 in a normal cell
-its inactived by its negative regulator, Mdm2
what occurs to p53 upon DNA damage or other stresses
-various pathways leads to the dissociation of the p53 and mdm2, activating p53
Once activated, what does p53 do
induces a cell cycle arrest to allow either repair and survival or apoptosis to discard the damage cell
what is the role of the Mdm2
its a E3 ubiquitin ligase, it promotes the ubiquiitination of p53 which leads to the degradation of p53. This keeps p53 levels low in undamaged cells
how does active p53 effect mdm2 levels
active p53 stimulates the Mdm2 gene expression
what is the cellular response to DNA damage to both p53 and Mdm2
- p53 is phosphorylated at serine 15 by the ATM or ATR kinase
- Mdm2 is also phosphorylated
- Both these phosphorylation disrupts the interactions
What occurs to Mdm2 in cancer
- over-expression of Mdm2 which functionally inactivates the p53 pathways
- this prevents cell cycle arrest and the induction of apoptosis in response to oncogene activation/DNA damage
what is p14ARF
a tumour supressor
p14ARF expression is induced by what
oncogenes as a result of increased cellular proliferation
what is p14ARF role in tumour suppression
disrupts the interactions between p53 and Mdm2
how does ARF effect Mdm2
inhibits its ubiquitin ligase activity
How does ARF activity effect p53
results in increased levels of transcriptionally active p53
In almost all cancer cells find ways to inactivated p53. What are these ways?
- Viral infection (E6) or a loss of function mutation of ATM decreases p53
- Loss of function mutation for ARF and amplification of Mdm2 causes p53 to be inactive
- There could also be a loss of function mutation as well as defects in sub-cellular localisation of p53
which domain in p53 is the most mutated in cancer
DNA-binding domain
what is Li-Fraumeni syndrome (LFS)
hereditary cancer predisposition
what is LFS most commonly caused by
Loss of function mutation in a gene called TP53, which is the gene responsible for p53 protein
What percentage of families with LFS will have a mutation in the TP53 gene
70%
how do the NF-kB and p53 pathways interact
There has to be a balance between them as they work as opposites
- they’re activity are integrated
