期刊
MOLECULAR CELL
卷 51, 期 4, 页码 409-422出版社
CELL PRESS
DOI: 10.1016/j.molcel.2013.08.010
关键词
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资金
- National Institutes of Health [1RO1CA137098, UL1-TR000157, GM089763]
- American Cancer Society [RSG-09-022-01-CNE]
- Harry J. Lloyd Charitable Trust
- National Health and Medical Research Council of Australia (NHMRC)
- National Basic Research Program of China [2010CB530400]
- Key Program of Natural Science Foundation of China [30930111]
- Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) [IRT1270]
- NHMRC
- Medical Research Council [G0801865] Funding Source: researchfish
- MRC [G0801865] Funding Source: UKRI
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.
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