Mechanisms of Oncogene Activation

Abstract

The activation of oncogenes involves genetic changes to cellular protooncogenes. The consequence of these genetic alterations is to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes in human neoplasms: (1) mutation, (2) gene amplification, and (3) chromosome rearrangements. These mechanisms result in either an alteration of protooncogene structure or an increase in protooncogene expression (Figure 6-5). Because neoplasia is a multistep process, more than one of these mechanisms often contribute to the genesis of human tumors by altering a number of cancer-associated genes. Full expression of the neoplastic phenotype, including the capacity for metastasis, usually involves a combination of protooncogene activation and tumor suppressor gene loss or inactivation. Figure 6-5Schematic representation of the main mechanisms of oncogene activation (from protooncogenes to oncogenes). The normal gene (protooncogene) is depicted with its transcibed portion (rectangle). In the case of gene amplification, the latter can be duplicated 100-fold, resulting in an excess of normal protein. A similar situation can occur when following chromosome rearrangements such as translocation, the transcription of the gene is now regulated by novel regulatory sequences belonging to another gene. In the case of point mutation, single aminoacid substitutions can alter the biochemical properties of the gene product, causing, in the example, its constitutive enzymatic activation. Chromosome rearrangements, such as translocation and inversion, can then generate fusion transcripts resulting in chimeric oncogenic proteins.