- D3 regulates keratinocyte differentiation and proliferation, but the precise mechanisms by which it does so are not well defined and the outcomes appear to be dependent on experimental conditions including the presence of growth factors. Calcium and protein kinase C (PKC) also regulate keratinocyte differentiation, and are likely to modulate these actions of D3. D3 induces the phospholipase C (PLC) family, enzymes which cleave phosphatidyl inositol bis phosphate (PIP2) into diacylglycerol (DAG) and inositol tris phosphate (1P3). These second messengers activate PKC and increase intracellular calcium (Cai). PLCg-1 is the most abundant member of the PLC family in keratinocytes, is regulated by calcium as well as D3, and is unique within the PLC family in its interaction with growth factor receptors such as EGFR and NGFR (trk). These characteristics have led the investigators to propose the following hypothesis. PLCg-l plays a critical role in the interaction between D3 and selected growth factors in their regulation of keratinocyte proliferation and differentiation. Dr. Bikle will test this hypothesis by achieving the following two objectives: 1. Determine the role of PLCg-1 in mediating the ability of D3 to regulate proliferation and differentiation. This will be accomplished by altering the production or activity of PLCg-1 in the cell and evaluating the effect of such maneuvers on the ability of D3 to regulate proliferation and differentiation. 2. determine whether the interaction between D3 and the growth factors EGF and NGF requires PLCg. To achieve this aim the ability of EGF and NGF to modulate the effect of D3 on proliferation and differentiation will be tested, the impact of induction of PLCg-1 by D3 on the acute effects of EGF and NGF with respect to increased Cai and PKC activity will be determined, and the requirement for PLCg-1 in the interactions between D3 and the growth factors EGF and NGF with respect to proliferation and differentiation will be evaluated.
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