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 language | English |
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Pages (from-to) | 409-422 |
Number of pages | 14 |
Journal | Molecular Cell |
Volume | 51 |
Issue number | 4 |
DOIs | |
Publication status | Published - 22 Aug 2013 |
Keywords
- ONCOGENE-INDUCED SENESCENCE
- BRAF-MUTANT MELANOMA
- CELLULAR SENESCENCE
- MALIGNANT-MELANOMA
- TUMOR-SUPPRESSOR
- RED HAIR
- VARIANTS
- KERATINOCYTES
- ACTIVATION
- MECHANISMS