Mechanisms regulating c-met overexpression in liver-metastatic B16-LS9 melanoma cells.
Liver selected B16-LS9 melanoma cells show a dramatic overexpression of the proto-oncogene c-met, the cellular receptor for hepatocyte growth factor/scatter factor. As a consequence, c-met becomes constitutively active, and the cells become more responsive to hepatocyte growth factor stimulation. We have investigated the molecular mechanisms regulating c-met expression in both the parental line B16-F1, which has low expression levels, and the liver-specific B16-LS9, overexpressing c-met. Overexpression is observed at the protein and mRNA levels, however without further evidence of gene amplification or rearrangement. c-met promoter activity was higher in B16-LS9 than B16-F1 cells, and also a nuclear run-off showed higher transcription levels in B16-LS9 cells. Moreover, we found that c-met mRNA had a longer half-life in B16-LS9 cells, thus indicating also the involvement of post-transcriptional regulation mechanisms. Finally, we found evidence that autonomous activation of the melanocortin receptor-1 (MCR-1) is at least partially responsible for c-met upregulation in B16-LS9 cells, since treatment of the cells with a potent MSH antagonist (the agouti peptide) has strong down-regulatory effects.
Elia
G
G
Friedrich Miescher Institute, Novartis Research Foundation, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Ren
Y
Y
Lorenzoni
P
P
Zarnegar
R
R
Burger
M M
MM
Rusciano
D
D
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008546:Melanoma, Experimental / Q000473:pathology*; D011401:Promoter Regions, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D019859:Proto-Oncogene Proteins c-met