Proliferation of normal cells is regulated at multiple points, any of which may be abnormal or absent in transformed cells. Thus study of normal cell growth is required to understand the mechanisms by which neoplastic cell escape growth control. The long-term objectives of this research are to understand how the proto-oncogenes c-myc and c-fos, which are associated with an early stage of cell proliferation in both lymphocytes and fibroblasts and whose viral counterparts are clearly implicated in neoplastic transformation, function in growth and activation of untransformed murine lymphocytes. Clonal murine T lymphocytes which respond to several growth-promoting signals in the absence of accessory cells will be used for these studies. myc and fos genes will be introduced into them using retroviral vectors by cocultivation with retrovirus-producing Psi-2 cells. Infected subclones constitutively expressing these oncogenes will be examined (1) for alterations in their growth responses to activating stimuli (Concanavalin A, clone-specific antibodies to the T cell receptor, Interleukin 2 (IL-2), the calcium ionophore A23187 plus phorbol myristate acetate), and (2) for expression of activation associated markers (IL-2 and IL-3 release, induction of IL-3 and Gamma-interferon genes, expression of cell-surface IL-2 receptors). In addition the inhibitors cyclosporin A and tetraethylammonium ion, which inhibit proliferation of the clones by acting at distinct points in the activation sequence, will be tested for whether they block induction of c-myc and c-fos in response to the growth-promoting stimuli listed above. If they do, they will be tested for whether their action is specific for lymphocytes, by determining whether they block induction of the same c-myc and c-fos genes in fibroblasts in response to the competence-inducing signals platelet-derived growth factor and phorbol myristate acetate.
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