Open AccessA novel P53/ POMC /Gαs/ SASH 1 autoregulatory feedback loop activates mutated SASH 1 to cause pathologic hyperpigmentation
Author(s) -
Zhou Ding'an,
Wei Zhiyun,
Kuang Zhongshu,
Luo Huangchao,
Ma Jiangshu,
Zeng Xing,
Wang Ke,
Liu Beizhong,
Gong Fang,
Wang Jing,
Lei Shanchuan,
Wang Dongsheng,
Zeng Jiawei,
Wang Teng,
He Yong,
Yuan Yongqiang,
Dai Hongying,
He Lin,
Xing Qinghe
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13022
Subject(s) - gene , biology , phenotype , signal transduction , mutation , genetics , cancer research
p53‐Transcriptional‐regulated proteins interact with a large number of other signal transduction pathways in the cell, and a number of positive and negative autoregulatory feedback loops act upon the p53 response. P53 directly controls the POMC /α‐ MSH productions induced by ultraviolet ( UV ) and is associated with UV ‐independent pathological pigmentation. When identifying the causative gene of dyschromatosis universalis hereditaria ( DUH ), we found three mutations encoding amino acid substitutions in the gene SAM and SH 3 domain containing 1 ( SASH 1), and SASH 1 was associated with guanine nucleotide‐binding protein subunit‐alpha isoforms short (Gαs). However, the pathological gene and pathological mechanism of DUH remain unknown for about 90 years. We demonstrate that SASH 1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH 1 is regulated by a novel p53/ POMC /α‐ MSH /Gαs/ SASH 1 cascade to mediate melanogenesis. A novel p53/ POMC /Gαs/ SASH 1 autoregulatory positive feedback loop is regulated by SASH 1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/ POMC /Gαs/ SASH 1 autoregulatory positive feedback loop is regulated by SASH 1 mutations to induce pathological hyperpigmentation phenotype.