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p53 regulates ERK 1/2/ CREB cascade via a novel SASH 1/ MAP 2K2 crosstalk to induce hyperpigmentation

2017; Wiley; Volume: 21; Issue: 10 Linguagem: Inglês

10.1111/jcmm.13168

1582-4934

Ding’an Zhou, Zhongshu Kuang, Xing Zeng, Ke Wang, Jiangshu Ma, Huangchao Luo, Mei Chen, Yan Li, Jiawei Zeng, Shu Li, Fu-Jun Luan, Yong He, Hongying Dai, Beizhong Liu, Hui Li, Lin He, Qinghe Xing,

Microbial Metabolism and Applications

Abstract We previously reported that three point mutations in SASH 1 and mutated SASH 1 promote melanocyte migration in dyschromatosis universalis hereditaria ( DUH ) and a novel p53/ POMC /Gαs/ SASH 1 autoregulatory positive feedback loop is regulated by SASH 1 mutations to induce pathological hyperpigmentation phenotype. However, the underlying mechanism of molecular regulation to cause this hyperpigmentation disorder still remains unclear. In this study, we aimed to investigate the molecular mechanism undergirding hyperpigmentation in the dyschromatosis disorder. Our results revealed that SASH 1 binds with MAP 2K2 and is induced by p53‐ POMC ‐ MC 1R signal cascade to enhance the phosphorylation level of ERK 1/2 and CREB . Moreover, increase in phosphorylated ERK 1/2 and CREB levels and melanogenesis‐specific molecules is induced by mutated SASH 1 alleles. Together, our results suggest that a novel SASH 1/ MAP 2K2 crosstalk connects ERK 1/2/ CREB cascade with p53‐ POMC ‐ MC 1R cascade to cause hyperpigmentation phenotype of DUH .