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J. Biol. Chem., Vol. 281, Issue 1, 121-128, January 6, 2006

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The Guanine Nucleotide Exchange Factor CNrasGEF Regulates Melanogenesis and Cell Survival in Melanoma Cells^*

From the Program in Cell Biology, The Hospital for Sick Children, and the Biochemistry Department, University of Toronto, Toronto, Ontario M5G 1X8, Canada

cAMP-dependent Ras activation has been demonstrated in numerous cell types, particularly of neuronal (including melanoma cells) and endocrine origin, but the Ras activator involved has not been identified. In B16 melanoma cells, cAMP activates the Ras/Erk pathway, leading initially to stimulation but subsequently to long term (>24-h) inhibition of melanogenesis (dendrite extension and melanin production). Here we identify CNrasGEF as the Ras guanine nucleotide exchange factor (GEF) involved. We demonstrate that CNrasGEF is expressed endogenously in B16 melanoma cells and that cAMP-mediated activation of Ras and Erk1/2 in these cells can be augmented by CNrasGEF overexpression and reduced by its knockdown by RNA interference. Moreover, we show that CNrasGEF participates in the regulation of melanogenesis. Knockdown of CNrasGEF leads to increased dendrite extension and melanin production observed 50 h after forskolin/isobutylmethylxanthine treatment, suggesting that CNrasGEF inhibits melanogenesis in the long term. Independently, we find that overexpression of CNrasGEF leads to apoptosis, whereas its knockdown by RNAi enhances cell proliferation, independent of cAMP. Collectively, these results suggest that CNrasGEF regulates melanogenesis but that it also has a distinct role in regulating cell proliferation/apoptosis.

Received for publication, July 13, 2005 , and in revised form, October 27, 2005.

^* This work was supported in part by the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society and by the Canadian Institute of Health Research (CIHR). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported through a studentship, fully or in part, by the Ontario Student Opportunity Trust Fund-Hospital for Sick Children Foundation Student Scholarship Program.

² Supported by a fellowship from the CIHR.

³ A CIHR Investigator and now holder of a Canada Research Chair (Tier I) award. To whom correspondence should be addressed: Program in Cell Biology, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5098; Fax: 416-813-5771; E-mail: drotin{at}sickkids.ca.

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