Nearly half of the more than two dozen known mammalian oncogenes encode molecules containing recognizable protein typrosine kinase domains. The precise functions of these kinases are in no cases known, however some serve as specific receptors for growth factors and it is likely that all will participate in the regulation of cell proliferation. The lymphocyte-specific protein tyrosine kinase gene lck is rearranged and overexpressed in a subset of lymphoid malignancies and resides at a site of frequent chromosmal abnormalities in human lymphoid tumors (1p32-35). Thus the lck gene is implicated in the pathogenesis of lymphoid malignancy and hence in the control of lymphocyte proliferation. This proposal seeks support for the detailed characterization of the lck gene in man and mouse and the identification of regulatory regions controlling its expression. To investigate the function of the lck kinase, altered versions of the lck gene will be reintroduced into cells and transgenic mice under the control of heterologous regulatory elements. In addition, other members of the lck gene family, defined by structural homology and similar expression patterns, will be examined in detail. The long-range goal of these experiments is the molecular dissection of growth regulatory pathways within the lymphoid cell linage.
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