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.

[1]  A. Eisen,et al.  Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. , 1986, The Journal of biological chemistry.

[2]  J. Lautenberger,et al.  Mammalian ets-1 and ets-2 genes encode highly conserved proteins. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Ken Yagi,et al.  c-myc Is a Downstream Target of the Smad Pathway* 210 , 2002, The Journal of Biological Chemistry.

[4]  W. Birchmeier,et al.  Evidence for the identity of human scatter factor and human hepatocyte growth factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Y. Kaneda,et al.  Hepatocyte growth factor gene therapy of liver cirrhosis in rats , 1999, Nature Medicine.

[6]  D. Watson,et al.  Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. , 2003, The American journal of pathology.

[7]  T. Medsger,et al.  Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. , 1988, The Journal of rheumatology.

[8]  C. Brinckerhoff,et al.  Inhibition of rabbit collagenase (matrix metalloproteinase‐1; MMP‐1) transcription by retinoid receptors: Evidence for binding of RARs/RXRs to the −77 AP‐1 site through interactions with c‐Jun , 1996, Journal of cellular physiology.

[9]  E. Imai,et al.  Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats , 1996, Hepatology.

[10]  D. Watson,et al.  Fli-1 Inhibits Collagen Type I Production in Dermal Fibroblasts via an Sp1-dependent Pathway* , 2001, The Journal of Biological Chemistry.

[11]  J. Rutter,et al.  Cell‐type specific regulation of human interstitial collagenase‐1 gene expression by interleukin‐1β (IL‐1β) in human fibroblasts and BC‐8701 breast cancer cells , 1997 .

[12]  P. Boros,et al.  Hepatocyte growth factor: a multifunctional cytokine , 1995, The Lancet.

[13]  N. Kamatani,et al.  Expression of hepatocyte growth factor and its receptor (c-met) in skin fibroblasts from patients with systemic sclerosis. , 2002, The Journal of rheumatology.

[14]  T. Nakamura,et al.  Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. , 1984, Biochemical and biophysical research communications.

[15]  Michael Stoker,et al.  Scatter factor is a fibroblast-derived modulator of epithelial cell mobility , 1987, Nature.

[16]  P. Flemming,et al.  MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation--an immunohistochemical study. , 2002, Gynecologic oncology.

[17]  J. Westermarck,et al.  Differential regulation of interstitial collagenase (MMP-1) gene expression by ETS transcription factors , 1997, Oncogene.

[18]  H. Ronday,et al.  Modified proenzymes as artificial substrates for proteolytic enzymes: colorimetric assay of bacterial collagenase and matrix metalloproteinase activity using modified pro-urokinase. , 1997, The Biochemical journal.

[19]  H. Shinkai,et al.  Gene expression of types I and III collagen, decorin, matrix metalloproteinases and tissue inhibitors of metalloproteinases in skin fibroblasts from patients with systemic sclerosis , 1997, Archives of Dermatological Research.

[20]  V. Sementchenko,et al.  Ets1 Is an Effector of the Transforming Growth Factor β (TGF-β) Signaling Pathway and an Antagonist of the Profibrotic Effects of TGF-β* , 2002, The Journal of Biological Chemistry.

[21]  K. Matsumoto,et al.  Preventive and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis , 1997, Hepatology.

[22]  E. CARwni LEROYwith,et al.  Increased Collagen Synthesis by Scleroderma Skin Fibroblasts In Vitro A POSSIBLE DEFECT IN THE REGULATION OR ACTIVATION OF THE SCLERODERMA FIBROBLAST , 2022 .

[23]  G. Michalopoulos,et al.  Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. , 1989, Cancer research.

[24]  H. Ihn,et al.  Transcriptional regulation of the human alpha2(I) collagen gene. Combined action of upstream stimulatory and inhibitory cis-acting elements. , 1996, The Journal of biological chemistry.

[25]  T. Nakamura,et al.  HGF triggers activation of the COX‐2 gene in rat gastric epithelial cells: action mediated through the ERK2 signaling pathway , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  Y. Taniyama,et al.  Mitogenic and Antiapoptotic Actions of Hepatocyte Growth Factor Through ERK, STAT3, and Akt in Endothelial Cells , 2001, Hypertension.

[27]  M. Harigai,et al.  Increased levels of hepatocyte growth factor in sera of patients with systemic sclerosis. , 1999, The Journal of rheumatology.

[28]  N. Bellamy,et al.  A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. , 2001, Arthritis and rheumatism.

[29]  C. Brinckerhoff,et al.  Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells. , 2002, Biochimica et biophysica acta.

[30]  K. Tashiro,et al.  Molecular cloning and expression of human hepatocyte growth factor , 1989, Nature.

[31]  I. Kola,et al.  Regulation of gene expression by transcription factors Ets‐1 and Ets‐2 , 1994, Molecular reproduction and development.

[32]  J. Rosenbloom,et al.  Co-ordinate increase in the expression of type I and type III collagen genes in progressive systemic sclerosis fibroblasts. , 1986, The Biochemical journal.

[33]  I. Haznedaroglu,et al.  Effects of oral cyclophosphamide and prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis. , 2003, Arthritis and rheumatism.

[34]  J. Westermarck,et al.  Regulation of matrix metalloproteinase expression in tumor invasion , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  H. Ihn,et al.  Oncostatin M Stimulates Transcription of the Human α2(I) Collagen Gene via the Sp1/Sp3-binding Site* , 1997, The Journal of Biological Chemistry.

[36]  C. Hartl,et al.  Direct demonstration of transcriptional activation of collagen gene expression in systemic sclerosis fibroblasts: insensitivity to TGF beta 1 stimulation. , 1992, Biochemical and biophysical research communications.

[37]  Y. Wan,et al.  Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. , 2001, International journal of molecular medicine.

[38]  B. Wasylyk,et al.  The c‐Ets oncoprotein activates the stromelysin promoter through the same elements as several non‐nuclear oncoproteins. , 1991, The EMBO journal.

[39]  M. Roussel,et al.  DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma , 1994, Molecular and cellular biology.

[40]  M. Jinnin,et al.  Effects of hepatocyte growth factor on the expression of type I collagen and matrix metalloproteinase-1 in normal and scleroderma dermal fibroblasts. , 2005, The Journal of investigative dermatology.

[41]  Kyosuke Yamamoto,et al.  Hepatocyte growth factor induces collagenase (matrix metalloproteinase-1) via the transcription factor Ets-1 in human hepatic stellate cell line. , 2002, Journal of hepatology.

[42]  K. Matsumoto,et al.  Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. , 1995, Journal of biochemistry.

[43]  R. Ilaria,et al.  Interference with the constitutive activation of ERK1 and ERK2 impairs EWS/FLI-1-dependent transformation , 2000, Oncogene.

[44]  S. Jimenez,et al.  Transcriptional activation of the alpha 1(I) procollagen gene in systemic sclerosis dermal fibroblasts. Role of intronic sequences. , 1996, Arthritis and rheumatism.

[45]  D. Watson,et al.  Ets transcription factors cooperate with Sp1 to activate the human Tenascin-C promoter , 1999, Oncogene.

[46]  V. Sementchenko,et al.  ETS2 function is required to maintain the transformed state of human prostate cancer cells , 1998, Oncogene.

[47]  S. Hirono,et al.  Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. , 1988, The Journal of clinical investigation.

[48]  K. Takeda,et al.  Decreased collagenase expression in cultured systemic sclerosis fibroblasts. , 1994, The Journal of investigative dermatology.

[49]  H. Ihn,et al.  IL-4 Up-Regulates the Expression of Tissue Inhibitor of Metalloproteinase-2 in Dermal Fibroblasts Via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway1 , 2002, The Journal of Immunology.