Tumor-suppressor genes generally encode proteins that in one way or another inhibit cell proliferation. Loss-of-function mutations in one or more of these proliferation inhibitory proteins contribute to the development of many cancers. Prominent among the classes of proteins encoded by tumor-suppressor genes are these five:
Generally, one copy of a tumor-suppressor gene suffices to control cell proliferation, so both alleles of a tumor-suppressor gene must be lost or inactivated in order to promote tumor development. Thus tumorigenesis-promoting loss-of-function mutations in tumor-suppressor genes are recessive (see Table 24-1). In this context, recessive means that if there is even one working gene copy, producing about half the usual amount of protein product, tumor formation will be prevented. With some genes, however, half the normal amount of product is not enough, in which case the loss of just one of the two gene copies can lead to cancer. This kind of gene is said to be haplo-insufficient. The loss of one copy of the gene is decisive for the final phenotype, so this type of mutation is dominant. It is useful to remember, then, the two processes by which cancer-causing genes can be dominant: (1) loss of one copy of a haplo-insufficient tumor-suppressor gene, resulting in insufficient product to control cell proliferation, and (2) activation of a gene or protein that causes cell proliferation even in the presence of one normal allele—that is, a dominant oncogene (as described in the previous section). In many cancers, tumor-suppressor genes have deletions or point mutations that prevent production of any protein or lead to production of a nonfunctional protein. Another mechanism for inactivating tumor-suppressor genes is methylation of cytosine residues in their promoters or other control elements, which inhibits their transcription. Such methylation is commonly found in nontranscribed regions of DNA (see Chapter 9).