Oral communication, PS6 / C72

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

When CRAF takes over from BRAF in melanoma using ERK and PDE4

In melanocytes, the MAPK pathway is activated through BRAF because CRAF is inhibited by the cAMP pathway in these cells. On the contrary, in melanoma harboring Ras mutations the MAPK pathway is activated through CRAF and the cAMP pathway is inhibited. We now provide insight into the molecular mechanism of this Raf isoform switching and cAMP pathway disruption, which happens during melanocyte transformation. We show that mutant Ras drives ERK-mediated phosphorylation of BRAF on Ser151. This phosphorylation inhibits BRAF activity by blocking its ability to interact with RAS. Consequently, in mutant RAS melanoma cells, MAPK is activated through CRAF. Moreover, cAMP phosphodiesterase activity is elevated inhibiting cAMP signaling to allow CRAF reactivation in melanoma cells. Using PDE inhibitors and RNA interference in melanoma cells harboring mutant RAS, we identified PDE4B and PDE4D as the main suppressors of cAMP signaling. Inhibition of PDE4 during α-MSH stimulation resulted in reactivation of the cAMP pathway. Interestingly, we show that small hairpin RNA–mediated inhibition of PDE4 is sufficient to inhibit transformation of normal melanocytes by oncogenic Ras. Moreover, inhibition of PDE4 by inhibitors or RNA interference can induce cell death in melanoma cells, but not in melanocytes, highlighting a novel therapeutic approach to treat melanoma-harboring Ras mutations.

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