Matrix metalloproteinase-1 up-regulation by hepatocyte growth factor in human dermal fibroblasts via ERK signaling pathway involves Ets1 and Fli1.
In this study, we clarified the molecular mechanism(s) underlying the regulation of matrix metalloproteinase (MMP)-1 gene by hepatocyte growth factor (HGF) in cultured human dermal fibroblasts. HGF induced MMP-1 protein as well as mRNA at a transcriptional level via extracellular signal-regulated kinase (ERK) signaling pathway. The region in the MMP-1 promoter mediating the inducible responsiveness to HGF, defined by the transient transfection analysis of the serial 5' deletion constructs, contained an Ets binding site. Mutation of this Ets binding site abrogated the HGF-inducible promoter activity. Ets1 up-regulated the expression of MMP-1 promoter activity, whereas Fli1 had antagonistic effects on them. After HGF treatment, the protein level and the binding activity of Ets1 was increased and those of Fli1 was decreased, which were canceled by PD98059. These results suggest that HGF up-regulates MMP-1 expression via ERK signaling pathway through the balance of Ets1 and Fli1, which may be a novel mechanism of regulating MMP-1 gene expression.
Department of Dermatology, Faculty of Medicine, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Masatoshi
M
Jinnin
Hironobu
H
Ihn
Yoshihiro
Y
Mimura
Yoshihide
Y
Asano
Kenichi
K
Yamane
Kunihiko
K
Tamaki
D004268:DNA-Binding Proteins / Q000502:physiology*; D020405:Dermis / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; C078433:FLI1 protein, human; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020781:Matrix Metalloproteinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one