Flashcards in The p53 tumour suppressor protein - L10 Deck (20)
What was p53 originally assumed to be ?
What is the p53 protein?
it is a TF, which is very complicated- it carries out many different functions and is involved in everything to with cell division and cell survival
it has the ability to interact with both proteins and genes
Why is it called the "guardian of the genome" ?
because it acts to protect DNA
What mammalian process is it a key factor in and what does it do ?
key protein in stress responses
-coordinates the blocking of cell proliferation, stimulates DNA repair and promotes apoptotic cell death
What % of cancers how loss of p53 function ?
How many mutations have been linked to p53 and what do many result in ?
>2000 mutations have been identified and > 50% of such mutations cause the protein to have an altered half life from minutes to hours
What do different mutations in p53 correlate with?
they may correlate with different cancers and therefore molecular epidemiological approaches may provide info on the causative agents - identifying where the mutations are can help determine what caused the mutation
What is seen in p53 null mice ?
they have a median age of survival of 6 moths and contain many tumours by that point including lymphomas, sarcomas and carcinomas
the heterozygouse ko mice have a median age of survival of 18 months
mice survived birth therefore p53 is not involved in development
What appears to delay tumourigenesis in heterozygous p53 mice?
limiting their caloric intake
indicated that cutting you caloric intake to 1500 per day reduces the risk of cancer
How many different cellular and viral proteins does p53 interact with ?
at least 17 cellular and viral proteins and several genes
What increases p53 stability and what does it mean ?
- Ionizing radiation
- certain mutagens
-action of oncogenes
increasing the proteins stability is a bad thing
What is the structure of p53 like ?
each monomer has 3 domains
what are the 3 domains in the p53 monomers?
- unstructured n-terminal domain (1-93)= binds other proteins to form a transcription complex for transcription of other genes. it is proline rich
- DNA core binding domain (102-292)highly conserved= 3 loop based elements, 1st binds major grove of DNA, 2nd binds the minor grove of DNA and 3rd stabilises the 2nd
- unstructured c-terminal domain (320-356)= contains the regulatory and tetramerization region - involved in assembly of the tetramer
What are the p53 protein domain?
there are several different domains
- transcriptional activation, proline rich, DNA binding, tetramerization and negative regulation
How can p53 be modified?
by post translational modifications
- phosphorylation, acetylation and sumoylation
Where do most mutations in p53 occur ?
most occur in a few hot spots around the DNA binding region
- if you take p53 from a tumour cell and sequence it you can find the mutation in it
- residues 248 and 273 are most frequently mutated, they contact DNA directly
Where are the most common p53 mutations ?
high frequency at codons 175, 248 and 273
they code for amino acids within the DNA binding domain
175= specific hot spot for mutations in lung cancer
What are the risk factors for liver cancer?
aflatoxin and hepatitis B viral infection
What have the study of p53 mutations in china and japan and taiwan shown ?
in parts of china the majority of mutations are G:C to T:A, characterstic adducts between aflatoxin and guanine
whereas in japan and taiwan hepatitis b is the predominant causative agent