Up-regulation of MET expression by alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis.
The MET proto-oncogene encodes for the hepatocyte growth factor (HGF) receptor, a plasma membrane tyrosine kinase that is involved in melanocyte growth and melanoma development. In mouse melanoma cells, Met expression is increased by alphaMSH via the activation of the cAMP pathway. However, the mechanism by which cAMP regulates MET and the biological consequences of this increase were not known. In the present report, we show that alphaMSH regulates MET expression in both human melanocytes and mouse melanoma cells through a transcriptional mechanism that requires MITF. Furthermore, the adenovirus driven expression of MITF is sufficient to increase MET in melanoma cells. Functional analysis of the MET promoter allows us to identify an E-box motif conserved in both human and mouse promoter that mediates the effect of MITF. Interestingly, up-regulation of MET expression by cAMP leads to an exacerbated HGF signaling and allows HGF to protect melanocytes and melanoma cells from apoptosis. Thus, physiological stimuli or pathological events that would induce MITF expression may lead to increased MET expression thereby favoring melanoma survival. These observations strengthen the roles of MITF and MET in melanoma development.
Beuret
Laurent
L
INSERM, U597, Biologie et Pathologies des Cellules Mélanocytaires: de la Pigmentation Cutanée au Mélanome, Equipe labellisée par la Ligue Nationale contre le Cancer, Nice Cedex 2, France.
Flori
Enrica
E
Denoyelle
Christophe
C
Bille
Karine
K
Busca
Roser
R
Picardo
Mauro
M
Bertolotto
Corine
C
Ballotti
Robert
R
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D052816:Foreskin / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000494:pharmacology*; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection; D015854:Up-Regulation; D000521:alpha-MSH / Q000494:pharmacology*
C000715470:MAS1 protein, human; D051739:Microphthalmia-Associated Transcription Factor; D000090063:Proto-Oncogene Mas; D000521:alpha-MSH; D017228:Hepatocyte Growth Factor; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D019859:Proto-Oncogene Proteins c-met