Graeme Finlay 6 Flashcards
What is TP53?
It is the gene with a locus at 17p.13.1 and is the most frequently inactivated in human cancer it was previously believed to be an oncogene, but once a wild type was isolated it was actually found to be a tumour suppressor gene
What are the different mechanisms through which TP53 function is lost?
Point mutations and loss of heterozygosity, amplification of the MDM2 protein as seen in gliomas and sarcomas, the HPV E6 protein binds to p53 and causes its degradation in cervical cancer
What is familial Li-Fraumeni syndrome?
A condition where a mutant p53 is transmitted
What is the action of normal p53?
To preserve the genetic integrity of the cell or induce apoptosis if the cell becomes genetically compromised
How do cells in culture demonstrate the function of p53?
Cells in culture with an inducible p53, can be made to express p53 causing the cells to undergo cell cycle arrest or apoptosis
How do transgenic mice show the normal function of p53?
Mice which are hetero or homozygous for mutant p53 develop normally but have an accelerated rate of tumour appearance showing that the mutant is dominant
How does p53 control the centrosome?
Cell replication requires that the centrosome is replicated only once to form the mitotic spindle while in cells lacking p53 function often produce multiple centrosomes which can promote genetic instability
What is the biochemical role of p53?
P53 binds to DNA through both sequence specific and non-specific mechanisms. This binding is induced following DNA damage.
Wild type p53 will activate p21 which inhibits Cdk2, Gadd45 which enhances the rate of DNA repair relative to replication, Bax which is a pro-apoptotic member of the Bcl-2 family
How does sunburn demonstrate cancer cells selecting for p53 mutants?
Cells exposed to UV radiation which acts as a carcinogen, normal skin contains cells which have mutant p53 induced by UVB radiation. These mutants will apoptose less efficiently allowing clonal expansion of the mutant cells as they take over the areas the other cells previously held. This then gives a large population of mutant heterozygotes which can generate mutant homozygotes
How does outgrowth of increasingly malignant clones demonstrate selection of p53 mutants in cancer?
P53 mutants are selected for in the hypoxic regions of tumours as hypoxia can induce cell damage causing cells with a functional p53 to undergo apoptosis. This results in populating the tumour with more malignant cells.
