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Tumour Suppressor Genes
Tumour suppressor genes prevent the cell from excessive proliferation, and usually promote cell cycle arrest, senescence, differentiation or apoptosis. Unlike oncogenes, which typically need only one copy of the gene to become active, tumour suppressor genes do not lose their function until both copies are lost.
The 'Two Hit Hypothesis'
The first suggestion of tumour suppressor genes was put forward by Knudson and his two hit hypothesis. The hypothesis states that if there are two copies of a tumour suppressor gene in a cell, then both must be lost in order for a tumour to develop. In normal members of the population with two functioning genes, a sporadic 'hit' (eg mutation) must knock out both copies of the gene. In people with a heterozygous loss of one allele, loss of the single normal gene will lead to development of malignancy. As it is easier for a cell to lose a single copy of a gene, this places the person at higher risk of developing malignancy earlier in life.
Knudson studied patients with inherited forms of retinoblastoma, who are likely to develop retinoblastoma at an early age, as well as from multiple foci. This was initially considered an autosomal dominant disease, as the likelihood of developing tumours was very high at an early age, and did not skip generations. Knudson proposed that instead of an autosomal dominant disease, patients instead had both non-functional 'retinoblastoma' gene and a normally functioning gene on the other chromosome. Thus, instead of an autosomal disease, familial retinoblastoma is an autosomal recessive disease that simply increases the risk of developing malignancy by removing one of the steps in tumour prevention.
Common Tumour Suppressor Genes
RB1 (retinoblastoma 1) codes for the retinoblastoma associated protein. As described in cell-cycle-regulators, it plays a central role in the G1/S checkpoint by binding E2F1 and preventing transcription of S phase genes. RB1 is deactivated by phosphorylation by CDK2, CDK4 and CDK6 when they are bound with their relevant cyclins. RB1 is not commonly mutated in human tumours, although other oncogenes may often cause it to be irrelevant (eg. translocation of CCND) due to inactivation.
TP53 is another vital protein, and unlike RB1 it is the most common target of genetic alteration in human tumours. It may lead to temporary or permanent cell cycle arrest, or apoptosis. Mutations typically occur in the DNA binding region of TP53, preventing it from binding to its normal sites. The cell cycle arrest caused by TP53 is carried out by CDKN1A (p21) which inhibits the function of CDK/cyclin complexes. Senescence is less well understood, but may require ongoing activation of TP53 and epigenetic changes. P63 and p73 are newly found proteins that seem to have more tissue specificity than TP53, but their full role is yet to be determined.
The family of APC genes downregulate growth promoting signals to prevent excess cell proliferation. A resting cell typically has low levels of β-catenin in the cytoplasm. When APC is absent, or when the cell is exposed to growth signals, β-catenin accumulates and causes cell proliferation. APC is required to reduce the levels of β-catenin. Familial adenomatous polyposis, an autosomal dominant disorder with loss of one APC gene, leads to development of thousands of colonic polyps which nearly always lead to cancer formation. Most sporadic colon cancers also lose the APC gene.
The INK4A/ARF locus consists of two proteins, one of which inhibits phosphorylation of RB1 and the other which activates TP53. This may lead to impaired senescence and loss of cell cycle control.
TGF- β is a potent inhibitor of most cell proliferation proteins, including MYC, RAS, cyclins and CDKs. It also enhances the activity of the INK4A/ARF locus. A component of the TGF-β pathway is mutated in many tumours.
PTEN blocks the activity of the PI3K/AKT signal transduction pathway. It is frequently deactivated in tumours which require this pathway to promote self sufficiency.
PTCH1 and PTCH2 are involved in the regulation of TNF β and other tumour suppressor proteins. They are mutated in Gorlin’s syndrome, which predisposes to nevoid basal cell carcinoma.