VIRUSES AND TRANSFORMING GENES IN EXPERIMENTAL ONCOGENESIS AND HUMAN CANCER

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The goals of this project are to elucidate the machinsms of action of tumor viruses and to determine the cellular alterations responsible for naturally occurring human malignancies. topics of present interest include: (1) transforming genes of retroviruses and cancer cells; (2) the biology of endogenous retroviruses; (3) the molecular biology of retrovirus replication and transformation; and (4) the application of knowledge gained from these studies to the search for the causes and mechanisms involved in human neoplastic transformation. During the past year, our investigations have provided important new insights regarding sis and ras genes, as well as indentification of a new human oncogene, designated dbl, from a diffuse B cell lymphoma. Highlights of sis include: demonstration that expression of the normal human sis/PDGF-2 coding sequence induces cellular transformation; the polypeptide sequence of the v-sis transforming gene product of simian sarcoma virus (SSV) is divisible into four regions which are likely to represent structural domains of the protein; the v-sis transforming gene encodes the woolly monkey homologue of human PDGE polypeptide 2; and definition of possible cellular locations where the transforming activity of the sis/PDGF-2 protein may be exerted. Regarding ras: three human ras family protooncogenes were chromosomally mapped; ras oncogenes were detected, cloned and at least partially characterized in lung and mammary carcinoma cell lines, as well as tumors of the urinary tract; activation of ras oncognees in human tumors appears to be most commonly due to point mutations at one of two major "hot spots" (codons 12 and 61) in the ras coding sequence.