AI Article Synopsis
- * UVB exposure causes the normal MC1R to interact with PTEN, preventing its degradation, which in turn helps deactivate the PI3K/AKT signaling pathway; this protective mechanism is absent in RHC-associated MC1R variants.
- * The failure of RHC MC1R variants to regulate PI3K/AKT signaling can lead to different outcomes based on context: it may cause premature aging in normal melanocytes or promote cancerous changes when combined with the BRAF(V600E) mutation.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792490 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2013.08.010 | DOI Listing |
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