Recent studies have identified for the first time the normal function of a proto-oncogene. The v-sis gene of simian sarcoma virus (SSV) is responsible for the transforming function of this virus. The primary amino acid sequence predicted from nucleotide sequence analysis served as a basis for obtaining synthetic peptide antibodies which allowed identification of the v-sis coded protein, p28sis. Independently, studies on human platelet-derived growth factor (PDGF) have led to the elucidation of much of its amino acid sequence. Computer comparisons of the PDGF sequence with the predicted amino acid sequence of p28sis has revealed an extraordinary degree of homology. By analysis of the p28sis molecule itself, it has been possible to demonstrate a very close structural similarity between these proteins. Moreover, p28sis is processed in SSV-transformed cells to forms which closely approximate PDGF conformationally and functionally. The v-sis gene arose from an evolutionarily conserved, unique sequence cellular gene, designated c-sis. A structural analysis of human c-sis DNA clones has shown that regions corresponding to the v-sis coding sequence are arranged in five exons which stretch over approximately 12 kbp of the human genome. The nucleotide sequence of these exons has revealed that the human sis proto-oncogene is the structural gene for one of the two major polypeptides of PDGF. Using probes derived from sequences flanking the v-sis-related regions of human c-sis, it has been possible to identify an upstream exon of the c-sis transcriptional unit. This exon is not related to v-sis but is transcribed in certain human tumor cells. In attempts to assess the transforming potential of the normal c-sis human locus, it has been shown that transcriptional activation of a construct containing all of v-sis-related exons as well as the upstream c-sis exon leads to the acquisition of high titered transforming activity.