Tumor suppressor genes.
The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear to function as negative regulators of cell division or abnormal cellular growth in some differentiated cell types. Several types of cancers have been shown to be derived from cells that have extensively mutated both alleles of one or both of these genes, resulting in a loss-of-function mutation. In the case of the p53 gene, this mutational process appears to occur in two steps, with the first mutation at the p53 locus resulting in a trans-dominant phenotype. The mutant p53 gene product enters into an oligomeric protein complex with the wild-type p53 protein derived from the other normal allele and such a complex is inactive or less efficient in its negative regulation of growth control. This intermediate stage of carcinogenesis selects for the proliferation of cells with one mutant allele, enhancing the probability of obtaining a cancer cell with both alleles damaged. The DNA tumor viruses have evolved mechanisms to interact with the Rb and p53 negative regulators of cellular growth in order to enhance their own replication in growing cells. SV40 and adenovirus type 5 produce viral encoded proteins that also form oligomeric protein complexes with p53 and Rb, presumably inactivating their functions. These viral proteins are also the oncogene products of these viruses. Thus, the mechanisms by which cancer may arise in a host, via mutations or virus infections, have fundamental common pathways effecting the same cellular genes and gene products; Rb and p53.
Levine
A J
AJ
Department of Biology, Lewis Thomas Laboratory, Princeton University, New Jersey 08544-1014.
D000595:Amino Acid Sequence; D000818:Animals; D005091:Exons; D005134:Eye Neoplasms / Q000235:genetics; D006801:Humans; D007223:Infant; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D012175:Retinoblastoma / Q000235:genetics; D016160:Retinoblastoma Protein; D012689:Sequence Homology, Nucleic Acid; D013489:Suppression, Genetic; D016159:Tumor Suppressor Protein p53; D014981:Xenopus
D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010750:Phosphoproteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53