PGC-1 coactivators regulate MITF and the tanning response

Mol Cell. 2013 Jan 10;49(1):145-57. doi: 10.1016/j.molcel.2012.10.027. Epub 2012 Nov 29.

Abstract

The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1β are critical components of this melanogenic system in melanocytes. α-MSH signaling strongly induces PGC-1α expression and stabilizes both PGC-1α and PGC-1β proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1α and PGC-1β blocks the α-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1α induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1β gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Case-Control Studies
  • Cell Line, Tumor
  • Gene Expression
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / physiology*
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Melanins / biosynthesis
  • Melanocytes / enzymology
  • Melanocytes / metabolism
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mice, Inbred C57BL
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Monophenol Monooxygenase / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Protein Stability
  • RNA-Binding Proteins
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Suntan / genetics*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation
  • alpha-MSH / metabolism
  • alpha-MSH / physiology

Substances

  • Carrier Proteins
  • Heat-Shock Proteins
  • MITF protein, human
  • Melanins
  • Microphthalmia-Associated Transcription Factor
  • PPARGC1A protein, human
  • PPARGC1B protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA-Binding Proteins
  • Transcription Factors
  • alpha-MSH
  • Monophenol Monooxygenase