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Mol Cell. 2013 Aug 22;51(4):409-22. doi: 10.1016/j.molcel.2013.08.010.

MC1R is a potent regulator of PTEN after UV exposure in melanocytes.

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1
Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118, USA.

Abstract

The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.

PMID:
23973372
PMCID:
PMC3792490
DOI:
10.1016/j.molcel.2013.08.010
[Indexed for MEDLINE]
Free PMC Article

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