MC1R Is a potent regulator of PTEN after UV exposure in melanocytes

Juxiang Cao, Lixin Wan, Elke Hacker, Xiangpeng Dai, Stefania Lenna, Celia Jimenez-Cervantes, Yongjun Wang, Nick R Leslie, George X. Xu, Hans R. Widlund, Byungwoo Ryu, Rhoda M. Alani, Ken Dutton-Regester, Colin R. Goding, Nicholas K. Hayward, Wenyi Wei, Rutao Cui

Research output: Contribution to journalArticle

82 Citations (Scopus)

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 wildtype (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, hyper-activation 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.

Original languageEnglish
Pages (from-to)409-422
Number of pages14
JournalMolecular Cell
Volume51
Issue number4
DOIs
Publication statusPublished - 22 Aug 2013

Keywords

  • ONCOGENE-INDUCED SENESCENCE
  • BRAF-MUTANT MELANOMA
  • CELLULAR SENESCENCE
  • MALIGNANT-MELANOMA
  • TUMOR-SUPPRESSOR
  • RED HAIR
  • VARIANTS
  • KERATINOCYTES
  • ACTIVATION
  • MECHANISMS

Cite this