Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 1, Pages 121-128Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M507595200
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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, cAMPactivates 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 similar to 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.
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