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J. Biol. Chem., Vol. 278, Issue 52, 52792-52801, December 26, 2003

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RasGRP1 Represents a Novel Non-protein Kinase C Phorbol Ester Signaling Pathway in Mouse Epidermal Keratinocytes^*

Reshmi A. Rambaratsingh, James C. Stone, Peter M. Blumberg¶, and Patricia S. Lorenzo||

From the Natural Products Program, Cancer Research Center of Hawaii, Honolulu, Hawaii 96813, the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada, and the ^¶Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland 20892

The mouse skin model of carcinogenesis has been instrumental in our appreciation of the multistage nature of carcinogenesis. In this system, tumor promotion is a critical step in the generation of tumors and is usually achieved by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Although it is generally assumed that protein kinase C (PKC) is the sole receptor for TPA in this system, we sought to evaluate whether non-PKC pathways could also contribute to the effects of phorbol esters in skin. We documented expression of the high affinity non-PKC phorbol ester receptor and Ras activator RasGRP1 in mouse primary keratinocytes. Overexpression of RasGRP1 in keratinocytes increased the level of active GTP-loaded Ras. TPA treatment further elevated this Ras activation in a PKC-independent manner and induced the translocation and down-regulation of RasGRP1. Overexpression of RasGRP1 in keratinocytes also caused apoptosis. Finally, induction of keratinocyte differentiation by elevation of extracellular calcium suppressed expression of endogenous RasGRP1, whereas overexpression of RasGRP1 inhibited expression of the differentiation markers keratins 1 and 10 induced by high calcium in the medium. Taken together, our results demonstrate that RasGRP1 is an additional diacylglycerol/phorbol ester receptor in epidermal keratinocytes and suggest that activation of this novel receptor may contribute to some of the phorbol ester- and Ras-mediated effects in mouse epidermis.

Received for publication, July 29, 2003 , and in revised form, September 11, 2003.

^* This work was supported by NCI Shannon Award Grant R55-CA96841-01 from the National Institutes of Health (to P. S. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Cancer Research Center of Hawaii, Rm. 315, 1236 Lauhala St., Honolulu, HI 96813. Tel.: 808-586-5868; Fax: 808-586-2970; E-mail: plorenzo{at}crch.hawaii.edu.

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