Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13845-50. doi: 10.1073/pnas.1201917110. Epub 2013 Aug 1.
The melanocortin 1 receptor (MC1R) mediates the tanning response through induction of cAMP and downstream pigmentary enzymes. Diminished function alleles of MC1R are associated with decreased tanning and increased melanoma risk, which has been attributed to increased rates of mutation. We have found that MC1R or cAMP signaling also directly decreases proliferation in melanoma cell lines. MC1R overexpression, treatment with the MC1R ligand, or treatment with small-molecule activators of cAMP signaling causes delayed progression from G2 into mitosis. This delay is caused by phosphorylation and inhibition of cdc25B, a cyclin dependent kinase 1-activating phosphatase, and is rescued by expression of a cdc25B mutant that cannot be phosphorylated at the serine 323 residue. These results show that MC1R and cAMP signaling can directly inhibit melanoma growth through regulation of the G2/M checkpoint.
黑素皮质素 1 受体 (MC1R) 通过诱导 cAMP 和下游色素酶来介导晒黑反应。MC1R 功能减弱的等位基因与晒黑减少和黑色素瘤风险增加有关，这归因于突变率的增加。我们发现 MC1R 或 cAMP 信号也可直接抑制黑色素瘤细胞系的增殖。MC1R 过表达、用 MC1R 配体处理或用 cAMP 信号小分子激活剂处理会导致从 G2 期进入有丝分裂的延迟。这种延迟是由 cdc25B 的磷酸化和抑制引起的，cdc25B 是一种细胞周期蛋白依赖性激酶 1 激活的磷酸酶，通过表达不能在丝氨酸 323 残基磷酸化的 cdc25B 突变体可以得到挽救。这些结果表明，MC1R 和 cAMP 信号可以通过调节 G2/M 检查点直接抑制黑色素瘤的生长。
