SN-1,2-Diacylglycerols (sn-1,2-DAGs) are intracellular lipid second messengers and the endogenous ligand of protein kinase C (PKC). Various sn-1,2-DAGs mimic some of the biochemical and morphological effects of the potent tumor promoter 12-0-tetradecanoylphorbol-13-acetate on mouse skin. Recently, sn-1,2-didecanoylglycerol was demonstrated to be a potent complete tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. These results suggest that an interaction between PKC and exogenous or endogenous sn-1,2-DAG may be sufficient to promote tumors in DMBA-initiated mouse skin containing a mutated Ha-ras oncogene (*Ha-ras). The fact that sn-1,2-DAG treatment alone is sufficient to promote tumors in initiated mouse skin may be of importance in tissues where an altered formation or degradation of endogenous sn-1,2-DAGs could lead to an accumulation of the lipid second messenger. Such an accumulation could produce abnormal cell proliferation or differentiation and perhaps a promoting stimulus. Therefore, it is the overall objective of this proposal to determine the mechanism through which exogenous sn-1,2-DAGs promote tumors and if there is a role for endogenous sn-1,2-DAGs in carcinogenesis.
The specific aims of this proposal are to determine: 1) if the down regulation of epidermal PKC by sn-1,2-DAG is permissive for hyperplasia and epidermal growth factor (EGF)-induced mitogenesis in vivo, 2) whether DMBA-initiated tumors containing a *Ha-ras have increased levels of free endogenous sn-1,2-DAGs down regulation of epidermal PKC (due to increased endogenous sn-1,2-DAGs), over expression of TGFalpha, and if these changes are functionally coupled in an autocrine loop and 3) why more frequent application of the sn-1,2-DAGs is necessary to demonstrate their tumor promoting activity (may be due to rapid metabolism, poor cutaneous absorption, attenuated inflammatory response and/or fatty acyl moiety). It is hypothesized that due to a mutated *Ha-ra, there is an increase in free endogenous sn-1,2-DAGs and an over expression of TGFalpha. The endogenous/exogenous sn-1,2-DAGs down regulate PKC which allows the EGF receptor to remain in its high affinity form. These events are permissive for the mitogenic response induced by the over expression of TGFalpha. The mouse skin initiation-promotion model, skin organ explants and mouse keratinocytes in culture will be used to address these important issues.
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