MC1R Is a Potent Regulator of PTEN After UV Exposure in Melanocytes

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Gene Expression Regulation / radiation effects*
  • Humans
  • Immunoenzyme Techniques
  • Melanocytes / metabolism*
  • Melanocytes / radiation effects
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology*
  • Mice
  • Mutation / genetics
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor, Melanocortin, Type 1 / genetics
  • Receptor, Melanocortin, Type 1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Skin Pigmentation / physiology*
  • Skin Pigmentation / radiation effects
  • Ultraviolet Rays*
  • alpha-MSH / genetics
  • alpha-MSH / metabolism

Substances

  • RNA, Messenger
  • Receptor, Melanocortin, Type 1
  • alpha-MSH
  • Phosphatidylinositol 3-Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human