Tumor Suppressors and the two-hit model of tumorigenesis

Tumor Suppressor genes tend to encode proteins whose normal function is to inhibit the cell cycle or to induce apoptosis to prevent transmission of uncorrectable DNA defects. Direct inhibitors of the cell cycle include pRB, illustrated in figure 1.15. Other tumor suppressor genes encode components of inhibitory growth factor-signaling pathways, particularly those of transforming growth factor (TGF)-β and its associated cytoplasmic signaling molecules such as Smad2 and Smad4 (which is the DPC4 ‘deleted in pancreatic carcinoma’ gene). As noted in the previous section, neurofibromin encodes as Ras inhibitor which is mutated in neurofibromatosis. APC, the gene mutated in familial adenomatous  polyposis and 60% of sporadic colon  adenomas and carcinomas, is bought to operate as an oncogene by rendering cells less susceptible to apoptosis. P53, a key tumor suppressor gene, normally uses both mechanisms to override other signals which would otherwise stimulate cell proliferation; details of P53 activity are highlighted in figure 1.16. The importance fo P53 is illustrated by the fact that it is inactivated in over 50% of human tumors, including breast and colon carcinomas, and childhood leukaemias.

When an oncogene results from a mutation reducing the activity of a tumor suppressor, a single mutation usually is insufficient to generate oncogenic activity unless an additional mutation in activities the second copy of the gene. This ‘two-hit’ model of tumorigenesis, developed by Knudson, is illustrated in figure 1.17. If, on the other hand, an oncogene results from over activity of a proto-oncogene, a mutation in only one of the two copies may be sufficient to promote tumorigenesis. This is also true in an important exception to the two-hit rule, in the case of the tumor suppressor gene P53, since mutation in only one allele may be sufficient to result in a biological effect. This reflects the operation of the protein as a tetramer, so abnormalities in any one of the subunits may derange its function.