title: p53 regulates ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation.
abstract: We previously reported that three point mutations in SASH1 and mutated SASH1 promote melanocyte migration in dyschromatosis universalis hereditaria (DUH) and a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 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 SASH1 binds with MAP2K2 and is induced by p53-POMC-MC1R signal cascade to enhance the phosphorylation level of ERK1/2 and CREB. Moreover, increase in phosphorylated ERK1/2 and CREB levels and melanogenesis-specific molecules is induced by mutated SASH1 alleles. Together, our results suggest that a novel SASH1/MAP2K2 crosstalk connects ERK1/2/CREB cascade with p53-POMC-MC1R cascade to cause hyperpigmentation phenotype of DUH.
authors.affiliation: Clinical Research Center, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.|Yongchuan Hospital, Chongqing Medical University, Chongqing, China.|Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Ding'an
authors.identifier: 0000-0002-6614-9321
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Zhongshu
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Jiangshu
authors.initials: J
authors.lastname: Ma
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Huangchao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Dujiangyan People's Hospital, Cheng du, Sichuan, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Luan
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Dai
authors.affiliation: Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Beizhong
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Nephrology and Rheumatology, the First People's Hospital, Chenzhou, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
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: D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010859:Pigmentation Disorders / Q000151:congenital / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D012873:Skin Diseases, Genetic / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C474743:SASH1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C482128:MAP2K2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048370:MAP Kinase Kinase 2
keywords: ERK1/2/CREB cascade; SASH1-MAP2K2 crosstalk; hyperpigmentation; p53-POMC-MC1R cascade