The p53 tumour suppressor protein - L10

Question 1

What was p53 originally assumed to be ?

Answer 1

an oncogene

Question 2

What is the p53 protein?

Answer 2

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

Question 3

Why is it called the “guardian of the genome” ?

Answer 3

because it acts to protect DNA

Question 4

What mammalian process is it a key factor in and what does it do ?

Answer 4

key protein in stress responses

-coordinates the blocking of cell proliferation, stimulates DNA repair and promotes apoptotic cell death

Question 5

What % of cancers how loss of p53 function ?

Answer 5

55%

Question 6

How many mutations have been linked to p53 and what do many result in ?

Answer 6

> 2000 mutations have been identified and > 50% of such mutations cause the protein to have an altered half life from minutes to hours

Question 7

What do different mutations in p53 correlate with?

Answer 7

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

Question 8

What is seen in p53 null mice ?

Answer 8

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

Question 9

What appears to delay tumourigenesis in heterozygous p53 mice?

Answer 9

limiting their caloric intake

indicated that cutting you caloric intake to 1500 per day reduces the risk of cancer

Question 10

How many different cellular and viral proteins does p53 interact with ?

Answer 10

at least 17 cellular and viral proteins and several genes

Question 11

What increases p53 stability and what does it mean ?

Answer 11

-UV
- Ionizing radiation
- certain mutagens
-hypoxia
-action of oncogenes
-transfection
increasing the proteins stability is a bad thing

Question 12

What is the structure of p53 like ?

Answer 12

tetramer

each monomer has 3 domains

Question 13

what are the 3 domains in the p53 monomers?

Answer 13

• 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

Question 14

What are the p53 protein domain?

Answer 14

there are several different domains

- transcriptional activation, proline rich, DNA binding, tetramerization and negative regulation

Question 15

How can p53 be modified?

Answer 15

by post translational modifications

- phosphorylation, acetylation and sumoylation

Question 16

Where do most mutations in p53 occur ?

Answer 16

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

Question 17

Where are the most common p53 mutations ?

Answer 17

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

Question 18

What are the risk factors for liver cancer?

Answer 18

aflatoxin and hepatitis B viral infection

Question 19

What have the study of p53 mutations in china and japan and taiwan shown ?

Answer 19

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

Question 20

What chromosome is p53 located on ?

Answer 20

chromosome 17