Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118, USA.
Mol Cell. 2013 Aug 22;51(4):409-22. doi: 10.1016/j.molcel.2013.08.010.
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.
携带黑色素皮质素受体 (MC1R) 变体的个体，尤其是那些与红发、白皙皮肤和较差的晒黑能力（RHC 特征）相关的个体，更容易患黑色素瘤；然而，其潜在机制尚不清楚。在这里，我们报告说，UVB 暴露会触发磷酸酶和张力蛋白同源物 (PTEN) 与野生型 (WT) 而非与 RHC 相关的 MC1R 变体相互作用，从而保护 PTEN 免受 WWP2 介导的降解，导致 AKT 失活。引人注目的是，MC1R 变体未能抑制 PI3K/AKT 信号的生物学后果高度依赖于上下文。在原代黑素细胞中，PI3K/AKT 信号的过度激活会导致过早衰老；在存在 BRAF(V600E) 的情况下，MC1R 缺陷诱导的升高的 PI3K/AKT 信号驱动致癌转化。这些研究确立了 MC1R-PTEN 轴作为黑色素细胞对 UVB 暴露反应的中央调节剂，并揭示了 MC1R 变体与黑色素瘤发生之间关联的分子基础。
