c-Met expression is regulated by Mitf in the melanocyte lineage.
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.
McGill
Gaël G
GG
Department of Pediatric Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Haq
Rizwan
R
Nishimura
Emi K
EK
Fisher
David E
DE
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000737:chemistry; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
D017931:DNA Primers; D051739:Microphthalmia-Associated Transcription Factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met