p53 regulates ERK1/2/CREB cascadeviaa novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation

Autor: Jiawei Zeng, Hui Li, Qinghe Xing, Xing Zeng, Zhongshu Kuang, Huangchao Luo, Fujun Luan, Hongying Dai, Ding'an Zhou, Yan Li, Lin He, Yong He, Ke Wang, Jiangshu Ma, Mei Chen, Bei-zhong Liu, Shu Li
Rok vydání: 2017
Předmět:
0301 basic medicine
MAP Kinase Kinase 2
CREB
Models
Biological

Melanocyte migration
Dyschromatosis universalis hereditaria
03 medical and health sciences
0302 clinical medicine
Hyperpigmentation
ERK1/2/CREB cascade
Cell Line
Tumor

medicine
Humans
SASH1‐MAP2K2 crosstalk
Cyclic AMP Response Element-Binding Protein
Extracellular Signal-Regulated MAP Kinases
p53‐POMC‐MC1R cascade
biology
Chemistry
Tumor Suppressor Proteins
Point mutation
Skin Diseases
Genetic

Original Articles
Cell Biology
medicine.disease
Phenotype
Cell biology
Crosstalk (biology)
HEK293 Cells
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
biology.protein
Molecular Medicine
Phosphorylation
Original Article
RNA Interference
Tumor Suppressor Protein p53
medicine.symptom
Pigmentation Disorders
Protein Binding
Signal Transduction
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-1838
DOI: 10.1111/jcmm.13168
Popis: 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.
Databáze: OpenAIRE