Studies from our laboratories have shown that the simian sarcoma virus (SSV) - transforming protein, p28sis, closely corresponds to the human platelet-derived growth factor (PDGF). The similarity has been demonstrated in amino acid sequence, structure, and cross reactivity to PDGF-antiserum. In other studies we have shown that the SSV-infected cells release molecules, which like PDGF stimulate DNA synthesis in target cells in culture, compete for binding to PDGF-receptors of normal fibroblasts and induce phosphorylation of fibroblast membrane proteins at tyrosine residue. The observations described here indicate that PDGF and the transforming protein of the simian sarcoma virus have arisen from the same or closely related cellular genes. This finding provided a basis for the understanding of the mechanisms by which the SSV onc gene induces cellular transformation. This mechanism may involve activation of sis transcription which results in the production of PDGF-like polypeptides causing the sustained abnormal proliferation of cells responsive to the growth stimulatory effects of the PDGF-like mitogens. If so, sis activation might be implicated as a step in the process leading normal human cells of certain tissue types towards malignancy. We propose to investigate the production, processing and release of PDGF-like proteins in cultures of human malignant cells. Identification of the PDGF-like proteins produced by the malignant cells will be carried out by immunoprecipitation using specific PDGF-antisera. The malignant cells to be studied are of mesenchymal origin or derived from human lymphocytes infected by the human T-cell lymphoma/leukemia virus, HTLV-1. These cells exhibit transcriptional activity of the sequences homologous to the SSV-sequences which have been correlated to the PDGF gene sequences. Intracellular PDGF-like proteins and the released products will be characterized for their ability to stimulate DNA synthesis, cell membrane protein phosphorylation, and for binding with PDGF-receptors.
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