Normal cell division ft Tumor-suppressor genes normally produce factors that inhibit cell division.

Excessive cell proliferation

^ Mutant alleles are recessive (both alleles must be mutated to produce excessive cell proliferation).

21.24 Both oncogenes and tumor-suppressor genes contribute to cancer but differ in their modes of action and dominance.

Some oncogenes and functions of their corresponding proto-oncogenes

Oncogene Cellular Location Function of Proto-oncogene sis Secreted Growth factor erbB Cell membrane Part of growth-factor receptor erbA Cytoplasm Thyroid hormone receptor src Cell membrane Protein tyrosine kinase ras Cell membrane GTP binding and GTPase myc Nucleus Transcription factor fos Nucleus Transcription factor jun Nucleus Transcription factor bcl-1 Nucleus Cell cycle become incorporated into the viral genome through recombination. Within the viral genome, the proto-oncogene may mutate to an oncogene that, when inserted back into a cell, causes rapid cell division and cancer. Because the proto-oncogenes are more likely to undergo mutation or recombination within a virus, viral infection is often associated with the cancer.

Proto-oncogenes can be converted into oncogenes in viruses by several different ways. The sequence of the proto-oncogene may be altered or truncated as it is being incorporated into the viral genome. This mutated copy of the gene may then produce an altered protein that causes uncontrolled cell proliferation. Alternatively, through recombination, a proto-oncogene may end up next to a viral promoter or enhancer, which then causes the gene to be overexpressed. Finally, sometimes the function of a proto-oncogene in the host cell may be altered when a virus inserts its own DNA into the gene, disrupting its normal function.

Many oncogenes have been identified by experiments in which selected fragments of DNA are added to cells in culture. Some of the cells take up the DNA and, if these cells become cancerous, then the DNA fragment that was added to the culture must contain an oncogene. The fragments can then be sequenced, and the oncogene can be identified. More than 70 oncogenes have now been discovered (Table 21.8).

Tumor-suppressor genes are more difficult than onco-genes to identify because they inhibit cancer and are recessive; both alleles must be mutated before the inhibition of cell division is removed. Because it is the failure of their function that promotes cell proliferation, tumor-suppressor genes cannot be identified by adding them to cells and looking for cancer.

One of the first tumor-suppressor genes to be identified was the retinoblastoma gene. In 1985, Raymond White and Webster Cavenne showed that large segments of chromosome 13 were missing in cells of retinoblastoma tumors, and later the tumor-suppressor gene was isolated from these segments. A number of tumor-suppressor genes have now been discovered in this way (Table 21.9).

Genes controlling the cell cycle Genes that control the cell cycle often serve as proto-oncogenes or tumor-suppressor genes. Let's briefly revisit the regulation of the cell cycle, which was discussed in Chapter 2. The cell cycle is regulated by cyclins, whose concentration oscillates during the cell cycle, and cyclin-dependent kinases (CDKs), which have a relatively constant concentration. Cyclins bind to CDKs, producing activated protein kinases that initiate key events in the cell cycle. Genes that encode cyclins and factors that inhibit or stimulate the formation of activated CDKs are often oncogenes and tumor-suppressor genes, respectively. Mutated cyclin genes have been associated with cancers of the immune system, breast, stomach, and esophagus; genes, such as p16 and p21, that encode inhibitors of CDKs are mutated or missing in many cancer cells.

Some proto-oncogenes and suppressor genes have roles in apoptosis. Cells have the ability to assess themselves and, when they are abnormal or damaged, they normally undergo apoptosis (see p. 000). Cancer cells frequently have chromosome mutations, DNA damage, and other cellular anomalies that would normally stimulate apoptosis and

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