c-Met expression is regulated by Mitf in the melanocyte lineage

J Biol Chem. 2006 Apr 14;281(15):10365-73. doi: 10.1074/jbc.M513094200. Epub 2006 Feb 2.

Abstract

Hepatocyte growth factor (HGF)/c-Met signaling is thought to be a key pathway in both melanocyte development and melanoma metastasis. Here, HGF stimulation of melanocytes was seen to up-regulate c-Met expression. In an effort to decipher the mechanism by which HGF up-regulates its receptor, we found that c-Met is a direct transcriptional target of Mitf. This was confirmed with chromatin immunoprecipitation experiments of the human c-Met promoter, as well as by the ability of adenovirally expressed Mitf to modulate endogenous c-Met protein levels in melanocytes. Disruption of Mitf blocked HGF-dependent increases in endogenous c-Met message and protein levels, indicating that HGF regulates its own receptor levels via Mitf. Finally, dominant-negative inhibition of Mitf resulted in profound resistance of melanocytes and melanoma cells to HGF-dependent matrix invasion, suggesting a physiologic role for this pathway in melanocytic development and melanoma.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • DNA Primers / chemistry
  • Gene Expression Regulation
  • Genes, Dominant
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Immunoblotting
  • Kinetics
  • MAP Kinase Signaling System
  • Melanocytes / metabolism*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Models, Genetic
  • Neoplasm Metastasis
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-met / chemistry*
  • Proto-Oncogene Proteins c-met / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transcription, Genetic
  • Up-Regulation

Substances

  • DNA Primers
  • Microphthalmia-Associated Transcription Factor
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met