Editors' ChoiceCancer

From Moles to Melanoma

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Sci. Signal.  10 Sep 2013:
Vol. 6, Issue 292, pp. ec218
DOI: 10.1126/scisignal.2004714

Melanocytes are specialized skin cells that produce the pigment that provides skin color and that increases skin color in response to exposure to the ultraviolet (UV) rays in sunlight. The RHC variants of the melanocortin-1 receptor (MC1R) are associated with red hair, fair skin, and poor tanning ability as well as increased risk of melanoma. One method by which cells cope with damage stimulated by stresses such as UV exposure and avert oncogenesis when certain oncoproteins become excessively activated is to undergo senescence. Some types of moles, in particular melanocytic nevi, result from the accumulation of senescent melanocytes in the skin. Cao et al. found that after exposure to UVB, skin samples from mice engineered with a nonfunctional MC1R or human epidermal cells with the RHC variant R151C-MC1R had less of the phosphatase and tumor suppressor PTEN and more of the active, phosphorylated form of the oncoprotein Akt than did skin from wild-type mice or the cells expressing wild-type MC1R. Coimmunoprecipitation or affinity pull-down experiments indicated that PTEN interacted with MC1R, but not with the RHC mutant forms, in cells exposed to both the MC1R ligand α-MSH and UVB. Furthermore, PTEN abundance and Akt phosphorylation were inversely related to the ability of MC1R to interact with PTEN, suggesting that the MC1R interaction stabilized PTEN. PTEN interacted with the E3 ubiquitin ligase WWP2, and UVB combined with α-MSH reduced the interaction between PTEN and WWP2, but not in cells expressing the RHC variant MC1Rs. In response to UVB and α-MSH, cells depleted of MC1R exhibited a decrease in cell proliferation and an increase in cells in G1, a senescence response that was prevented by introducing wild-type MC1R, but not the RHC variants or PTEN. To understand how this senescence pathway may be bypassed to lead to cancer, the authors examined the relationship between BRAFV600E, a constitutively active form of BRAF that is found in the majority of melanomas, and MC1R RHC variants. When compared to cells with only the BRAFV600E mutation, cells with BRAFV600E and either depleted of MC1R or expressing the MC1R RHC variants had increased activated Akt and ERK (extracellular signal–regulated kinase), a survival signal and proliferation signal. These cells formed anchorage-independent colonies, consistent with a transformed phenotype. These data provide a potential molecular mechanism for the increased susceptibility of redheads with fair skin to develop skin cancer.

J. Cao, L. Wan, E. Hacker, X. Dai, S. Lenna, C. Jimenez-Cervantes, Y. Wang, N. R. Leslie, G. X. Xu, H. R. Widlund, B. Ryu, R. M. Alani, K. Dutton-Regester, C. R. Godling, N. K. Hayward, W. Wei, R. Cui, MC1R is a potent regulator of PTEN after UV exposure in melanocytes. Mol. Cell 51, 409–422 (2013). [PubMed]