A novel P53/POMC/Gαs/SASH1 autoregulatory feedback loop activates mutated SASH1 to cause pathologic hyperpigmentation.
Zhou D1,2, Wei Z3, Kuang Z1, Luo H1, Ma J1, Zeng X1, Wang K1, Liu B1, Gong F1, Wang J1, Lei S1, Wang D4, Zeng J5, Wang T2, He Y1, Yuan Y1, Dai H1, He L2,3, Xing Q2.
1Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.2Children’s Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.3Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.4Department of Laboratory Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China.5Dujiangyan People’s Hospital, Cheng du, Sichuan, China.
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 SH3 domain containing 1 (SASH1), and SASH1 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 SASH1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH1 is regulated by a novel p53/POMC/α-MSH/Gαs/SASH1 cascade to mediate melanogenesis. A novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype.
© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
DUH ; SASH1; hyperpigmentation; p53