The proposed research will explore the mechanism by which nerve growth factor (NGF) suppresses neoplasia and blocks cell proliferation in certain neoplastic target cells. The model system to be studied is the PC12 rat pheochromocytoma cell line, which stops dividing and differentiates into neuron-like cells in response to NGF. PC12 cells have been used extensively for studies of the mechanism of neuronal differentiation. An underexplored property of PC12 cells is the reversibility of the non-dividing, differentiated phenotype; removal of NGF results in dedifferentiation and resumption of neoplastic proliferation. The sequence of compositional changes underlying dedifferentiation and the temporal and mechanistic relationship of dedifferentiation to cell cycle reentry will be explored. A second underexplored aspect of PC12 cell biology is the meachanism of NFG-induced cessation of cell proliferation. The relationship of differentiation to cessation of cell proliferation, as well as several possible antiproliferative mechanisms will be explored, including: 1) Possible NGF-antivated suppression of mitogenic sinals from EGF and insulin via loss of EGF and insulin cell surface receptors; 2) Possible NGF-triggered reduction of p53, a protein which may play a role in promotion of proliferation; 3) Attempted isolation of mutant sublines with defective kinase C and cyclic AMP kinase-activated antiproliferative pathways to determine possible effects on the antiproliferative action of NGF; 4) PC12 mutants which lack the antiproliferative response to NGF will be selected and, along with previously isolated, spontaneously arising NGF-resistant variants, will be analyzed for possible defects leading to loss of the antiproliferative response. PC12 cells and related sublines constitute a potentially valuable model for examining the role of defective programs of differentiation in loss of growth control in cancer cells, as well as for understanding the mechanisms by which normal differentiation pathways may suppress cell proliferation and the neoplastic phenotype.
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