Downregulation of SIK2 expression promotes the melanogenic program in mice

Pigment Cell Melanoma Res. 2010 Dec;23(6):809-19. doi: 10.1111/j.1755-148X.2010.00760.x. Epub 2010 Aug 31.

Abstract

cAMP response element-binding protein (CREB) promotes melanogenesis by inducing microphthalmia-associated transcription factor (Mitf ) gene expression. We report here that the CREB-specific coactivator TORC and its repressor, salt-inducible kinase 2 (SIK2), are fundamental determinants of the melanogenic program in mice. Exposure of B16 melanoma cells to ultraviolet (UV) light results in the immediate nuclear translocation of TORC1, which is inhibited by SIK2. Overexpression of dominant-negative TORC1 also inhibits UV-induced Mitf gene expression and melanogenesis. α-MSH signaling regulates hair pigmentation, and the decrease in α-MSH activity in hair follicle melanocytes switches the melanin synthesis from eumelanin (black) to pheomelanin (yellow). Mice with the lethal yellow allele of agouti (A(y)) have yellow hair because of impaired activation of the α-MSH receptor. To examine the involvement of SIK2 in the regulation of the melanogenesis switch in vivo, we prepared SIK2-knockout mice, and the Sik2(-/-) genotype was introduced into A(y)/a mice. The resultant Sik2(-/-); A(y)/a mice had brown hair, indicating that SIK2 represses eumelanogenesis in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Down-Regulation / genetics*
  • Down-Regulation / radiation effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Hair
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Melanins / biosynthesis*
  • Melanoma / enzymology
  • Melanoma / genetics
  • Melanoma / pathology
  • Mice
  • Pigmentation / radiation effects
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Ultraviolet Rays
  • alpha-MSH / metabolism

Substances

  • Isoenzymes
  • Melanins
  • Transcription Factors
  • alpha-MSH
  • Cyclic AMP
  • salt-inducible kinase-2, mouse
  • Protein-Serine-Threonine Kinases