Question

Name 4 genetic events that can eliminate the activity of a tumor suppressor gene?​

Answer 1

Answer:

Tumor Suppressor Genes

The activation of cellular oncogenes represents only one of two distinct types of genetic alterations involved in tumor development; the other is inactivation of tumor suppressor genes. Oncogenes drive abnormal cell proliferation as a consequence of genetic alterations that either increase gene expression or lead to uncontrolled activity of the oncogene-encoded proteins. Tumor suppressor genes represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development. In many tumors, these genes are lost or inactivated, thereby removing negative regulators of cell proliferation and contributing to the abnormal proliferation of tumor cells.

individuals as a result of a second somatic mutation leading to the loss of the remaining normal Rb allele. Noninherited retinoblastoma, in contrast, is rare, since its development requires two independent somatic mutations to inactivate both normal copies of Rb in the same cell

The functional nature of the Rb gene as a negative regulator of tumorigenesis was initially indicated by observations of chromosome morphology. Visible deletions of chromosome 13q14 were found in some retinoblastomas, suggesting that loss (rather than activation) of the Rb gene led to tumor development (Figure 15.35). Gene-mapping studies further indicated that tumor development resulted from loss of normal Rb alleles in the tumor cells, consistent with the function of Rb as a tumor suppressor gene. Isolation of the Rb gene as a molecular clone in 1986 then firmly established that Rb is consistently lost or mutated in retinoblastomas. Gene transfer experiments also demonstrated that introduction of a normal Rb gene into retinoblastoma cells reverses their tumorigenicity, providing direct evidence for the activity of Rb as a tumor suppressor.

Although Rb was identified in a rare childhood cancer, it is also involved in some of the more common tumors of adults. In particular, studies of the cloned gene have established that Rb is lost or inactivated in many bladder, breast, and lung carcinomas. The significance of the Rb tumor suppressor gene thus extends beyond retinoblastoma, apparently contributing to development of a substantial fraction of more common human cancers. In addition, as noted earlier in this chapter, the Rb protein is a key target for the oncogene proteins of several DNA tumor viruses, including SV40, adenoviruses, and human papillomaviruses, which bind to Rb and inhibit its activity (Figure 15.36). Transformation by these viruses thus results, at least in part, from inactivation of Rb at the protein level rather than from mutational inactivation of the Rb gene.

Characterization of Rb as a tumor suppressor gene served as the prototype for the identification of additional tumor suppressor genes that contribute to the development of many different human cancers (Table 15.5). Some of these genes were identified as the causes of rare inherited cancers, playing a role similar to that of Rb in hereditary retinoblastoma. Other tumor suppressor genes have been identified as genes that are frequently deleted or mutated in common noninherited cancers of adults, such as colon carcinoma. In either case, it appears that most tumor suppressor genes are involved in the development of both inherited and noninherited forms of cancer. Indeed, mutations of some tumor suppressor genes appear to be the most common molecular alterations leading to human tumor development.