Dominant gain-of-function mutations in proto-oncogenes and recessive loss-of-function mutations in tumor-suppressor genes are oncogenic. Among the proteins encoded by proto-oncogenes are positive-acting growth factors and their receptors, signal-transduction proteins, transcription factors, and cell-cycle control proteins. An activating mutation of one of the two alleles of a proto-oncogene converts it to an oncogene, which can induce transformation in cultured cells or cancer in animals. Activation of a proto-oncogene into an oncogene can occur by point mutation, gene amplification, and gene translocation. The first recognized oncogene, v-src, was identified in Rous sarcoma virus, a cancer-causing retrovirus. Retroviral oncogenes arose by transduction of cellular proto-oncogenes into the viral genome and subsequent mutation. The first human oncogene to be identified encodes a constitutively active form of Ras, a signal-transduction protein. This oncogene was isolated from a human bladder carcinoma. Slow-acting retroviruses can cause cancer by integrating near a proto-oncogene in such a way that gene transcription is activated continuously and inappropriately. Tumor-suppressor genes encode proteins cell cycle if DNA is damaged or chromosomes are abnormal, receptors for secreted hormones that function to inhibit cell proliferation, proteins that promote apoptosis, and DNA repair enzymes. Inherited mutations causing retinoblastoma led to the identification of RB, the first tumor-suppressor gene to be recognized.
