p53 regulates ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation

J Cell Mol Med. 2017 Oct;21(10):2465-2480. doi: 10.1111/jcmm.13168. Epub 2017 Apr 6.


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.

Keywords: ERK1/2/CREB cascade; SASH1-MAP2K2 crosstalk; hyperpigmentation; p53-POMC-MC1R cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • HEK293 Cells
  • Humans
  • Hyperpigmentation / genetics
  • Hyperpigmentation / metabolism*
  • MAP Kinase Kinase 2 / genetics
  • MAP Kinase Kinase 2 / metabolism*
  • Models, Biological
  • Mutation
  • Pigmentation Disorders / congenital
  • Pigmentation Disorders / genetics
  • Pigmentation Disorders / metabolism
  • Protein Binding
  • RNA Interference
  • Signal Transduction / genetics
  • Skin Diseases, Genetic / genetics
  • Skin Diseases, Genetic / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • SASH1 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • MAP2K2 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 2

Supplementary concepts

  • Dyschromatosis universalis hereditaria