title: A novel P53/POMC/Gαs/SASH1 autoregulatory feedback loop activates mutated SASH1 to cause pathologic hyperpigmentation.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.|Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Ding'an
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Zhongshu
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Huangchao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Jiangshu
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Beizhong
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Gong
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Shanchuan
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of Laboratory Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Dujiangyan People's Hospital, Cheng du, Sichuan, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Laboratory Medicine, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Dai
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Xing
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002460:Cell Line; D002864:Chromogranins / Q000378:metabolism*; D025461:Feedback, Physiological; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008543:Melanins / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010859:Pigmentation Disorders / Q000151:congenital / Q000235:genetics / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011485:Protein Binding / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D012873:Skin Diseases, Genetic / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D002864:Chromogranins; D008543:Melanins; C474743:SASH1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D011333:Pro-Opiomelanocortin; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: 
  DUH
  ; SASH1; hyperpigmentation; p53