Tumour suppressors Flashcards
What are tumour suppressor genes?
Genes which normally function to restrict growth. They are recessive – loss of function mutations predispose to cancer formation.
They are sporadic and germline mutations and cancers tend to have indicating mutations in 1 or more tumour suppressor genes.
Deletions or point mutations result in no protein or a protein with altered function.
What are the main classes of tumour suppressor genes?
Growth/ development suppressors – TGFb, patched1
Cell cycle checkpoint proteins – pRb, p53
Cell cycle inhibitors – CDKI, p16.
DNA repair enzymes – Xeroderma pigmentosa
Developmental pathways – patched
Inducers of apoptosis – Bax, p53.
What is hereditary predisposition?
Inheriting germline mutation in one allele. Subsequent somatic mutation in the other.
APC – precancerous intestinal polyps; increased risk of colon cancer.
BRCA1 – 60% probability of inheriting breast cancer compared to 2% with two wild type alleles.
What is retinoblastoma?
Tumours can develop in the retina, 40% of cases are inherited. It is a recessive trait.
Retinal tumours early in life in one or both eyes.
Each tumour derived from a single cell.
What is p53?
It is evolved to prevent tumour development and usually present in low levels in cells, complex to inhibitor protein MDM2.
Stress signals inhibit MDM2 allowing activation of p53.
Stabilised p53 protein levels increase and p53 acts as a transcriptional regulator. It as active as a tetramer.
How can p53 be involved in the inhibition of cell growth?
P53 activation normally inhibits cell growth by cell cycle arrest and induction of apoptosis.
P53 regulates the expression of :
P16,21,27 cyclin dependent kinase inhibitor
MDM2
Bad/Bax
What is the link between p53 and cancer?
Mutations of p53 occur in more than 50% of humans, mutant p53 is more stable. Many mutations occur in DNA binding region and mutant p53 molecules can interfere with wild type p53 action.
Li Fraumeni syndrome is an inherited disorder of mutated p53 and affected patients are predisposed to tumour formation.
What are p53 mutations?
P53 is activated by carcinogens.
In lung cancer there are mutations in p53. The benzo(a) pryine in cigarette smoke is metabolised in liver generating a potent mutagen. The mutation causes G > T transversions in DNA and the hot spots are in p53, R175, R248, R273.
In liver cancer aflatoxin leads to G > T transversions at R249 or p53.
What is the significance of p53 status?
P53 is rarely mutated in cervical cancer, however polymorphism affects susceptibility to HPV E6 mediated degradation. Chemotherapeutic agents and radiation rely on inducing apoptosis for the cytotoxic effects.
Lack of p53 often makes tumour cells resistant through the lack of functional apoptotic pathway.
