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16.4: Oncogenes

  • Page ID
    16194
  • Oncogenes are generally dominant gain-of-function mutations of normal cellular genes called protooncogenes. These protooncogenes are themselves positive regulators of the cell cycle, but they are regulated by other factors, either extracellular signals or intracellular mechanisms. Mutations that turn them into oncogenes specifically remove all or some of this regulation. They thus become overactive, and try to push the cell cycle forward leading to increased proliferation. These mutations can also be classified into a few general mechanistic categories.

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    Figure 12. Conversion of protooncogenes to oncogenes. (1) Due to mutation of the coding region, the protein has higher physiological activity. (2) Gene duplication leads to multiple copies of the gene each expressed normally, making many more copies of the protein than normal. (3) Mutation of the regulatory region or translocation of a stronger enhancer or promoter to the protooncogene can lead to enhance transcription, and therefore more protein. (4) Translocation of another gene inline with part of the coding region, can put the activity of the protooncogene under the control of modifiers of the translocated gene, and thus lead to overactivity.

    These (fig. 12) are mutations to the coding region that increase physiological activity, gene duplications resulting in more copies of the gene at the DNA level and thus more at the protein level, mutations to the regulatory region of the gene or that alter regulation of gene expression, thus increasing copy number of the protein, and finally, translocations that replace part of the coding region, resulting in a chimeric protein whose activity may be under a different control scheme than normal.

    Examples of two types of mutations are illustrated in Figure 13 with a mitogen receptor as the protooncogene. In the first case, the transmembrane portion of the receptor has been mutated, causing an amino acid change that alters the conformation not just of the transmembrane region, but of the cytoplasmic kinase domain, which becomes constitutively active, regardless of whether a ligand has bound outside or not. In the second case, the entire extracellular domain has been removed due to a mutation of an amino acid codon into a stop codon or translocation, and the resulting receptor is always active, also independent of ligand binding.

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    Figure 13. Conversion of a mitogen receptor protooncogene into an oncogene by point mutation leading to amino acid change in the transmembrane region (left) or by truncation of ligand-binding domain.

    Some kinds of retroviral infection can accomplish the conversion of a protooncogene to an oncogene by inserting viral DNA near the promoter region of the protooncogene. Because the viral promoters tend to be very strong, they can induce overexpression of the protooncogene product. In avian species, avian leukosis virus is known to cause tumors by insertion near the c-myc oncogene, while in humans, another retrovirus, HTLV (human T-lymphotropic virus), can cause acute disease (tropical spastic paraparesis), but may also cause T-cell leukemia and lymphoma.

    What functions are characteristic of protooncogenes? Mitogen receptors, as already described above, and exemplified by the receptor tyrosine kinases EGFR (epidermal growth factor receptor), VEGFR (vascular endothelial growth factor receptor), RON (recepteur d’origine nantais, a macrophage stimulating protein receptor), and ErbB2 (also HER2/neu, another human EGF receptor). Growth factors themselves may also be pro- tooncogenes, such as FGF-5, one of several oncogenes in the broblast growth factor family, or c-sis, an oncogenic form of PDGF (platelet-derived growth factor). Signal cascade proteins, often either tyrosine or serine/threonine kinases or other regulatory enzymes, are a large group of protooncogenes (e.g. Src family tyrosine kinases, BTK family tyrosine kinases, cyclin-dependent Ser/Thr kinases, Ras-family small GTPases). Finally, various transcription factors (e.g. Ets, Myc, E2F families), can effectively be mutated into oncogenes.