Investigations of human platelet-derived growth factor (PDGF) have provided an understanding of at least one mechanism involved in malignant transformation. It is suggested that in vivo, PDGF is delivered during platelet degranulation at the site of injury where it participates in the process of wound healing by stimulating the proliferation and migration of connective tissue cells. We have shown recently that PDGF and the transforming protein of the simian sarcoma virus (SSV) derive from the same or closely related cellular genes. This conclusion is based on the demonstration that PDGF and the SSV-transforming protein share extensive amino acid sequence homology, have common antigenic determinants and structural conformation, and exert identical biological functions. These findings suggest that the ability of the simian sarcoma virus to induce transformation derives from the incorporation of the PDGF gene within the retroviral genome. The resulting transforming onc gene (v-sis) region within the retrovirus genome codes for a PDGF-like mitogen and is capable of inducing neoplastic transformation by the continuous production of this potent mitogen, causing sustained cell proliferation. Consistent with the findings is the detection of v-sis-related messenger RNAs in human tumors of mesenchymal origin. Production of PDGF-like mitogen by these human malignant cells in culture has been established. More recent studies have demonstrated that these cells synthesize, process, and release PDGF-like polypeptides which are recognized by specific PDGF antisera. The partial sequence of c-sis cDNA clones from a human osteosarcoma cell line reveal the sequence identity between the carboxy terminal region of the PDGF-2 chain and the osteosarcoma c-sis gene product. These data provide the first direct demonstration of the presence of c-sis transcripts in a spontaneous human malignant cell line that can potentially be translated to a full-length PDGF-2 precursor protein. These combined findings demonstrate that activation of sis transcription can cause the sustained abnormal proliferation of human cells which are target cells of PDGF action. Thus, sis activation may be involved in the process leading normal cells of mesenchymal origin toward malignancy. (J)
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