Inhibition of PAX3 by TGF-beta modulates melanocyte viability

Mol Cell. 2008 Nov 21;32(4):554-63. doi: 10.1016/j.molcel.2008.11.002.

Abstract

The protein encoded by paired-box homeotic gene 3 (PAX3) is a key regulator of the microphthalmia-associated transcription factor (Mitf) in the melanocyte lineage. Here, we show that PAX3 expression in skin is directly inhibited by TGF-beta/Smads. UV irradiation represses TGF-beta in keratinocytes, and the repression of TGF-beta/Smads upregulates PAX3 in melanocytes, which is associated with a UV-induced melanogenic response and consequent pigmentation. Furthermore, the TGF-beta-PAX3 signaling pathway interacts with the p53-POMC/MSH-MC1R signaling pathway, and both are crucial in melanogenesis. The activation of p53-POMC/MSH-MC1R signaling is required for the UV-induced melanogenic response because PAX3 functions in synergy with SOX10 in a cAMP-response element (CRE)-dependent manner to regulate the transcription of Mitf. This study will provide a rich foundation for further research on skin cancer prevention by enabling us to identify targeted small molecules in the signaling pathways of the UV-induced melanogenic response that are highly likely to induce naturally protective pigmentation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation*
  • Genes, Regulator
  • Genes, Reporter
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Luciferases / metabolism
  • Melanocytes / metabolism
  • Melanocytes / physiology*
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors / antagonists & inhibitors*
  • Paired Box Transcription Factors / genetics*
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / genetics
  • Skin Pigmentation / genetics
  • Skin Pigmentation / physiology
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Ultraviolet Rays

Substances

  • PAX3 Transcription Factor
  • PAX3 protein, human
  • Paired Box Transcription Factors
  • SMAD4 protein, human
  • Smad4 Protein
  • Transforming Growth Factor beta
  • Luciferases