Abstract
Developmental and homeostatic remodeling of the extracellular matrix (ECM) is a highly regulated process orchestrated by a family of zinc-containing, calcium-dependent neutral proteases known as the matrix metallo-proteinases (MMP). This family of enzymes, which now contains twenty members, can collectively degrade all structural proteins of the ECM including interstitial collagens (I, II, III, and V), basement membrane collagens (IV), fibronectin, laminin, proteoglycan, and elastin (Table 1). The enzymatic activity of MMP family members is controlled by a group of inhibitor proteins known as the Tissue Inhibitors of Metalloproteinases (TIMPs), which consist of four family members (Table 2). Whereas all four TIMPs can inhibit all MMPs in vitro, preferential TIMP-MMP interactions and tissue-restricted TIMP expression suggest that each TIMP has a specific function (Table 2).
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References
Firestein G. S., Paine M. M., and Littman B. H. (1991) Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intra-articular corticosteroids. Arthritis Rheum. 34, 1094–2105.
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Wernicke D., Seyfert C., Hinzmann B., and Gromnica-Ihle E. (1996) Cloning of collagenase 3 from the synovial membrane and its expression in rheumatoid arthritis and osteoarthritis. J. Rheumatol., 23, 590–595.
Clark I. M., Powell L. K., Ramsey S., Hazleman B. L., and Cawston T. E. (1993) The measurement of collagenase, tissue inhibitor of metalloproteinases (TIMP), and collagenase-TIMP complex in synovial fluids from patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum. 36, 372–379.
Firestein G. S., Paine M. M., and Boyle D. L. (1994) Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arthritis Rheum. 37, 193–200.
Hembry R. M., Bagga M. R., Reynolds J. J., and Hamblen D. L. (1995) Immunolocalisation studies on six matrix metalloproteinases and their inhibitors, TIMP-1 and TIMP-2, in synovia from patients with osteo-and rheumatoid arthritis. Annals of the Rheumatic Diseases. 54, 25–32.
Coussens L. M. and Werb Z. (1996) Matrix metalloproteinases and the development of cancer. Chemistry & Biology. 3, 895–904.
Chambers A. F. and Matrisian L. M. (1997) Changing views of the role of matrix metalloproteinases in metastasis. J. Nat. Cancer Institute. 89, 1260–1270.
Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G., and Humphries S. (1991) Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc. Nat. Acad. Sci. USA 88, 8154–8158.
Libby P. (1995) Molecular bases of the acute coronary syndromes. Circulation. 91, 2844–2850.
Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., and Karin M. (1987) Phorbol ester-inducible genes contain a common cis elecent recognized by a TPA-modulated trans-acting factor. Cell, 49, 729–739.
Gutman A. and Wasylyk B. (1990) The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. Embo J. 9, 2241–2246.
Auble D. T. and Brinckerhoff C. E. (1991) The AP-1 sequence is necessary but not sufficient for phorbol induction of collagenase in fibroblasts. Biochem. 30, 4629–4635.
Mitchell P. G. and Cheung H. S. (1991) Tumor necrosis factor alpha and epidermal growth factor regulation of collagenase and stromelysin in adult porcine articular chondrocytes. J. Cell Phys. 149, 132–140.
Mauviel A., Kahari V. M., Chen Y. Q., Kurkinen M., Evans C. H., and Uitto J. (1992) Transcriptional activation of fibroblast stromelysin-1 and collagenase gene expression by a novel lymphokine, leukoregulin, Trans. Assoc. Am. Phys. 105, 100–109.
James T. W., Wagner R., White L. A., Zwolak R. M., and Brinckerhoff C. E. (1993) Induction of collagenase and stromelysin gene expression by mechanical injury in a vascular smooth muscle-derived cell line. J. Cell Phys. 157, 426–437.
Chamberlain S. H., Hemmer R. M., and Brinckerhoff C. E. (1993) Novel phorbol ester response region in the collagenase promoter binds Fos and Jun. J. Cell Biochem. 52, 337–351.
Vincenti M. P., Coon C. I., Lee O., and Brinckerhoff C. E. (1994) Regulation of collagenase gene expression by IL-1 beta requires transcriptional and post-transcriptional mechanisms Nucleic Acids Res. 22, 4818–4827.
Tremble P., Damsky C. H., and Werb Z. (1995) Components of the nuclear signaling cascade that regulate collagenase gene expression in response to integrin-derived signals J. Cell Biol. 129, 1707–1720.
White L. A. and Brinckerhoff C. E. (1995) Two activator protein-1 elements in the matrix metalloproteinase-1 promoter have different effects on transcription and bind Jun D, c-Fos, and Fra-2. Matrix Biol. 14, 715–725.
Doyle G. A. R., Pierce R. A., and Parks W. C. (1997) Transcriptional induction of collagenase-1 in differentiated monocyte-like (U937) cells is regulated by AP-1 and an upstream C/EBP-beta site. J. Biol. Chem. 272, 11,840–11,849.
Vincenti M. P., Schroen D. J., Coon C. I., and Brinckerhoff C. E. (1998) V-src activation of the collagenase-1) matrix metalloproteinase-1 promoter through PEA3 and STAT: Requirement of extracellular signal-regulated kinases and inhibition by retinoic acid receptors. Mol. Carcin. 21.
Pierce R. A., Sandefur S., Doyle G. A., and Welgus H. G. (1996) Monocytic cell type-specific transcriptional induction of collagenase. J. Clin. Invest. 97, 1890–1899.
Hurley M. M., Marcello K., Abreu C., Brinckerhoff C. E., Bowik C. C., and Hibbs M. S. (1995) Transcriptional regulation of the collagenase gene by basic fibroblast growth factor in osteoblastic MC3T3-E1 cells. Biochem. Biophys. Res. Com. 214, 331–339.
Overall C. M., Wrana J. L., and Sodek J. (1991) Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J. Biol. Chem. 266, 14,064–14,071.
Frisch S. M. and Ruley H. E. (1987) Transcription from the stromelysin promoter is induced by interleukin-1 and repressed by dexamethasone. J. Biol. Chem. 262, 16,300–16,304.
Quinones S., Saus J., Otani Y., Harris E. D., Jr., and Kurkinen M. ( 1989) Transcriptional regulation of human stromelysin. J. Biol. Chem. 264, 8339–8344.
Sirum K. L. and Brinckerhoff C. E. (1989) Cloning of the genes for human stromelysin and stromelysin 2: differential expression in rheumatoid synovial fibroblasts. Biochem. 28, 8691–8698.
Wasylyk C., Gutman A., Nicholson R., and Wasylyk B. (1991) The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins. Embo. J. 10, 1127–1134.
Sirum-Connolly K. and Brinckerhoff C. E. (1991) Interleukin-1 or phorbol induction of the stromelysin promoter requires an element that cooperates with AP-1. Nucleic Acids Res. 19, 335–341.
Buttice G., Quinones S., and Kurkinen M. (1991) TheAP-1 site is required for basal expression but is not necessary for TPA-response of the human stromelysin gene. Nucleic Acids Res. 19, 3723–3731.
Mauviel A., Kahari V. M., Kurkinen M., Evans C. H., and Uitto J. (1992) Leukoregulin, a T-cell derived cytokine, upregulates stromelysin-1 gene expression in human dermal fibroblasts: evidence for the role of AP-1 in transcriptional activation. J. Cell Biochem. 50, 53–61.
Buttice G. and Kurkinen M. (1993) A polyomavirus enhancer A-binding protein-3 site and Ets-2 protein have a major role in the 12-O-tetradecanoylphorbol-13-acetate response of the human stromelysin gene. J. Biol. Chem. 268, 7196–7204.
Quinones S., Buttice G., and Kurkinen M. (1994) Promoter elements in the transcriptional activation of the human stromelysin-1 gene by the inflammatory cytokine, interleukin-1. Biochem. J. 302, 471–477.
Buttice G., Duterque-Coquillaud M., Basuyaux J. P., Carrere S., Kurkinen M., and Stehelin D. (1996) Erg, an Ets-family member, differentially regulates human collagenase 1 (MMP1) and stromelysin 1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. Oncogene. 13, 2297–2306.
Kirstein M., Sanz L., Quinones S., Moscat J., Diaz-Meco M. T., and Saus J. (1996) Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene. J. Biol. Chem. 271, 18,231–18,236.
Gaire M., Magbanua Z., McDonnell S., McNeil L., Lovett D. H., and Matrisian L. M. (1994) Structure and expression of the human gene for the matrix metalloproteinase matrilysin. J. Biol. Chem. 269, 2032–2040.
Klein R. D., Borchers A. H., Sundareshan P., Bougelet C., Berkman M. R., Nagle R. B., and Bowden G. T. (1997) Interleukin-1beta secreted from monocytic cells induces the expression of matrilysin in the prostatic cell line LNCaP. J. Biol. Chem. 272, 14,188–14,192.
Sato H. and Seiki M. (1993) Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells. Oncogene. 8, 395–405.
He C. (1996) Molecular mechanism of transcriptional activation of human gelatinase B by proximal promoter. Cancer Letters. 106, 185–191.
Yokoo T. and Kitamura M. (1996) Dual regulation of IL-1 beta-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kappa B and AP-1, Am. J. Physiol. 270, F123–F130.
Monet-Kuntz C., Cuvelier A., Sarafan N., and Martin J. P. (1997) Metalloelastase expression in a mouse macrophage cell line—regulation by 4betaphorbol 12-myristate 13-acetate, lipopolysaccharide and dexamethasone. Eur. J. Biochem. 247, 588–595.
Grumbles R. M., Shao L., Jeffrey J. J., and Howell D. S. (1996) Regulation of rat interstitial collagenase gene expression in growth cartilage and chondrocytes by vitamin D3, interleukin-1 beta, and okadaic acid. J. Cell Biochem. 63, 395–409.
Pendas A. M., Balbin M., Llano E., Jimenez M. G., and LĂłpez-OtĂn C. (1997) Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). Genomics. 40, 222–233.
Johansson N., Westermarck J., Leppa S., Hakkinen L., Koivisto L., Lopez-Otin C., Peltonen J., Heino J., and Kahari V. M. (1997) Collagenase 3 (matrix metalloproteinase 13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor alpha and transforming growth factor beta. Cell Growth Differ. 8, 243–250.
Tardif G., Pelletier J. P., Dupuis M., Hambor J. E., and Martel-Pelletier J. (1997) Cloning, sequencing and characterization of the 5′-flanking region of the human collagenase-3 gene. Biochem. J. 323, 13–16.
Alitalo R., Partanen J., Pertovaara L., Holtta E., Sistonen L., Andersson L., and Alitalo K. (1990) Increased erythroid potentiating activity/tissue inhibitor of metalloproteinases and jun/fos transcription factor complex characterize tumor promoter-induced megakaryoblastic differentiation of K562 leukemia cells. Blood 75, 1974–1982.
Campbell C. E., Flenniken A. M., Skup D., and Williams B. R. (1991) Identification of a serum-and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene. J. Biol. Chem. 266, 7199–7206.
Colige A. C., Lambert C. A., Nusgens B. V., and Lapiere C. M. (1992) Effect of cell-cell and cell-matrix interactions on the response of fibroblasts to epidermal growth factor in vitro. Expression of collagen type I, collagenase, stromelysin and tissue inhibitor of metalloproteinases. Biochem. J. 285, 215–221.
Edwards D. R., Rocheleau H., Sharma R. R., Wills A. J., Cowie A., Hassell J. A., and Heath J. K. (1992) Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription. Biochim. Biophys. Acta. 1171, 41–55.
Clark I. M., Rowan A. D., Edwards D. R., Bech-Hansen T., Mann D. A., Bahr M. J., and Cawston T. E. (1997) Transcriptional activity of the human tissue inhibitor of metalloproteinases 1 (TIMP-1) gene in fibroblasts involves elements in the promoter, exon 1 and intron 1. Biochem. J. 324, 611–617.
Doyle G. A., Saarialho-Kere U. K., and Parks W. C. (1997) Distinct mechanisms regulate TIMP-1 expression at different stages of phorbol ester-mediated differentiation of U937 cells. Biochem. 36, 2492–2500.
Botelho F. M., Edwards D. R., and Richards C. D. (1998) Oncostatin M stimulates c-Fos to bind a transcriptionally responsive AP-1 element within the tissue inhibitor of metalloproteinase-1 promoter (In Process Citation). J. Biol. Chem. 273, 5211–5218.
Cook T. F., Burke J. S., Bergman K. D., Quinn C. O., Jeffrey J. J., and Partridge N. C. (1994) Cloning and regulation of rat tissue inhibitor of metalloproteinases-2 in osteoblastic cells. Arch. Biochem. Biophys. 311, 313–320.
Leco K. J., Khokha R., Pavloff N., Hawkes S. P., and Edwards D. R. (1994) Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J. Biol. Chem. 269, 9352–9360.
Su S., Dehnade F., and Zafarullah M. (1996) Regulation of tissue inhibitor of metalloproteinases-3 gene expression by transforming growth factor-beta and dexamethasone in bovine and human articular chondrocytes. DNA Cell Biol. 15, 1039–1048.
Huttenlocher A., Werb Z., Tremble P., Huhtala P., Rosenberg L., and Damsky C. H. (1996) Decorin regulates collagenase gene expression in fibroblasts adhering to vitronectin. Matrix Biol. 15, 239–250.
Anglard P., Melot T., Guerin E., Thomas G., and Basset P. (1995) Structure and promoter characterization of the human stromelysin-3 gene. J. Biol. Chem. 270, 20.337–20.344.
Guerin E., Ludwig M. G., Basset P., and Anglard P. (1997) Stromelysin-3 induction and interstitial collagenase repression by retinoic acid. Therapeutical implication of receptor-selective retinoids dissociating transactivation and AP-1-mediated transrepression. J. Biol. Chem. 272, 11,088–11,095.
Ahmad A., Marshall J. F., Basset P., Anglard P., and Hart I. R. (1997) Modulation of human stromelysin 3 promoter activity and gene expression by human breast cancer cells. Int. J. Cancer 73, 290–296.
Gutman A., Wasylyk C., and Wasylyk B. (1991) Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter. Mol. Cell Biol. 11, 5381–5387.
Gutman A. and Wasylyk B. (1991) Nuclear targets for transcription regulation by oncogenes. Trends Genet. 7, 49–54.
Vincenti M. P., Coon C. I., and Brinckerhoff C. E. (1998) NF-kB/p50 activates an element in the distal matrix metalloproteinase-1 promoter in interleukin-1ß-stimulated synovial fibroblasts. Arthritis Rheum. 41, 1987–1994.
Ponton A., Coulombe B., Steyaert A., Williams B. R., and Skup D. (1992) Basal expression of the gene (TIMP) encoding the murine tissue inhibitor of metalloproteinases is mediated through AP1-and CCAAT-binding factors. Gene. 116, 187–194.
Coulombe B., Ponton A., Daigneault L., Williams B. R., and Skup D. (1988) Presence of transcription regulatory elements within an intron of the virus-inducible murine TIMP gene. Mol. Cell Biol. 8, 3227–3234.
Kikuchi K., Kadono T., Furue M., and Tamaki K. (1997) Tissue inhibitor of metalloproteinase 1 (TIMP-1) may be an autocrine growth factor in scleroderma fibroblasts. J. Invest. Dermatol. 108, 281–284.
Wright J. K., Clark I. M., Cawston T. E., and Hazleman B. L. (1991) The secretion of the tissue inhibitor of metalloproteinases (TIMP) by human synovial fibroblasts is modulated by all-trans-retinoic acid. Biochim. Biophys. Acta. 1133, 25–30.
Auble D. T. and Brinckerhoff C. E. (1990) Regulation of Collagenase Gene Expression in Synovial Fibroblasts. Annals. NY Ac ad. Sci. 580, 355–373.
Jonat C., Stein B., Ponta H., Herrlich P., and Rahmsdorf H. J. (1992) Positive and negative regulation of collagenase gene expression. Matrix Supplement 1, 145–155.
Lotan R. (1996) Retinoids and their receptors in modulation of differentiation, development, and prevention of head and neck cancers. Anticancer Res. 16, 2415–2419.
Lotan R. (1996) Retinoids in cancer prevention. FASEB J. 10, 1031–1039.
Nicholson R. C., Mader S., Nagpal S., Leid M., Rochette-Egly C., and Chambon P. (1990) Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO J. 9, 4443–4454.
Pan L.-Y., Chamberlain S. H., Auble D. T., and Brinckerhoff C. E. (1992) Differential regulation of collagenase gene expression by retinoic acid receptors-alpha, beta, and gamma. Nucleic Acids Res. 20, 3105–3111.
Pan L., Eckhoff C., and Brinckerhoff C. E. (1995) Suppression of Collagenase Gene Expression by all-trans and 9-cis Retinoic Acid is Ligand Dependent and Requires Both RARs and RXRs. J. Cell Biochem. 57, 575–589.
Schroen D. J. and Brinckerhoff C. E. (1996) 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. J. Cell Phys. 169, 320–332.
Edwards D. R., Murphy G., Reynolds J. J., Whitham S. E., Docherty A. J., Angel P., and Heath J. K. (1987) Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 6, 1899–1904.
Kerr L. D., Miller D. B., and Matrisian L. M. (1990) TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence. Cell 61, 267–278.
Rydziel S., Varghese S., and Canalis E. (1997) Transforming growth factor beta1 inhibits collagenase 3 expression by transcriptional and post-transcriptional mechanisms in osteoblast cultures (published erratum appears in J. Cell Physiol. 1997 May;171(2):234). J. Cell Phys. 170, 145–152.
Rutter J. L., Benbow U., Coon C. I., and Brinckerhoff C. E. (1997) Cell-type specific regulation of human interstitial collagenase-1 gene expression by interleukin-1 beta (IL-1 beta) in human fibroblasts and BC-8701 breast cancer cells. J. Cell Biochem. 66, 322–336.
Hou X., Johnson A. C., and Rosner M. R. (1994) Induction of epidermal growth factor receptor gene transcription by transforming growth factor beta 1: association with loss of protein binding to a negative regulatory element. Cell Growth & Diff. 5, 801–809.
Delany A. M. and Brinckerhoff C. E. (1992) Post-transcriptional regulation of collagenase and stromelysin gene expression by epidermal growth factor and dexamethasone in cultured human fibroblasts. J. Cell Bioche. 50, 400–410.
Tamai K., Ishikawa H., Mauviel A., and Uitto J. (1995) Interferon-gamma coordinately upregulates matrix metalloprotease (MMP)-1 and MMP-3, but not tissue inhibitor of metalloproteases (TIMP), expression in cultured keratinocytes. J. Invest. Dermatol. 104, 384–390.
Shaw G. and Kamen R. (1986) A conserved AU sequence from the 3′untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–997.
Brewer G. (1991) An A+U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Mol. Cell Biol. 12, 2460–2466.
Delany A. M., Jeffrey J. J., Rydziel S., and Canalis E. (1995) Cortisol increases interstitial collagenase expression in osteoblasts by post-transcriptional mechanisms. J. Biol. Chem. 270, 26,607–26,612.
Varghese S., Delany A. M., Liang L., Gabbitas B., Jeffrey J. J., and Canalis E. (1996) Transcriptional and posttranscriptional regulation of interstitial collagenase by platelet-derived growth factor BB in bone cell cultures. Endocrinol. 137, 431–437.
Rydziel S., Varghese S., and Canalis E. (1997) Transforming growth factor beta1 inhibits collagenase 3 expression by transcriptional and post-transcriptional mechanisms in osteoblast cultures. J. Cell Phys. 170, 145–152.
Freije J. M., Diez-Itza I., Balbin M., Sanchez L. M., Blasco R., Tolivia J., and Lopez-Otin C. (1994) Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 269, 16,766–16,773.
Vincenti M. P., Coon C. I., Mengshol A. J., Yocum S., Mitchell P., and Brinckerhoff C. E. (1998) Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1). Biochem J. 331, 341–346.
Edwards D. R., Waterhouse P., Holman M. L., and Denhardt D. T. (1986) A growth-responsive gene (16C8) in normal mouse fibroblasts homologous to a human collagenase inhibitor with erythroid-potentiating activity: evidence for inducible and constitutive transcripts. Nucleic Acids Res. 14, 8863–8878.
Waterhouse P., Khokha R., and Denhardt D. T. (1990) Modulation of translation by the 5′ leader sequence of the mRNA encoding murine tissue inhibitor of metalloproteinases. J. Biol. Chem. 265, 5585–5589.
Baeuerle P. A. (1998) Pro-inflammatory signaling: last pieces in the NF-kappaB puzzle? Current Biol. 8, R19–22.
Su B. and Karin M. (1996) Mitogen-activated protein kinase cascades and regulation of gene expression. Current Opin. Immunol. 8, 402–411.
Robinson M. J. and Cobb M. H. (1997) Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9, 180–186.
Cobb M. H., Hepler J. E., Cheng M., and Robbins D. (1994) The mitogen-activated protein kinases. ERK1 andERK2. Seminars Cancer Biol. 5, 261–268.
Gupta S., Barrett T., Whitmarsh A. J., Cavanagh J., Sluss H. K., Derijard B., and Davis R. J. (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. Embo. J. 15, 2760–2770.
Han J., Lee J. D., Bibbs L., and Ulevitch R. J. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells., Science. 265, 808–811.
Matsuda S., Gotoh Y., and Nishida E. (1994) Signaling pathways mediated by the mitogen-activated protein (MAP) kinase kinase/MAP kinase cascade. J. Leukocyte Biol. 56, 548–553.
Minden A. and Karin M. (1997) Regulation and function of the JNK subgroup of MAP kinases. Biochim. Biophys. Acta. 1333, F85–F104.
Frost J. A., Geppert T. D., Cobb M. H., and Feramisco J. R. (1994) A requirement for extracellular signal-regulated kinase (ERK) function in the activation of AP-1 by Ha-Ras, phorbol 12-myristate 13-acetate and serum. Proc. Natl. Acad. Sci. USA 91, 3844–3848.
McCarthy S. A., Chen D., Yang B. S., Garcia Ramirez J. J., Cherwinski H., Chen X. R., Klagsbrun M., Hauser C. A., Ostrowski M. C., and McMahon M. (1997) Rapid phosphorylation of Ets-2 accompanies mitogen-activated protein kinase activation and the induction of heparin-binding epidermal growth factor gene expression by oncogenic Raf-1. Mol. Cell Biol. 17, 2401–2412.
Rabault B., Roussel M. F., Quang C. T., and Ghysdael J. (1996) Phosphorylation of Ets1 regulates the complementation of a CSF-1 receptor impaired in mitogenesis. Oncogene 13, 877–881.
Whitmarsh A. J., Shore P., Sharrocks A. D., and Davis R. J. (1995) Integration of MAP kinase signal transduction pathways at the serum response element. Science 269, 403–407.
Sluss H. K., Barrett T., Derijard B., and Davis R. J. (1994) Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol. Cell Biol. 14, 8376–8383.
Minden A., Lin A., Claret F. X., Abo A., and Karin M. (1995) Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81, 1147–1157.
Raingeaud J., Gupta S., Rogers J. S., Dickens M., Han J., Ulevitch R. J., and Davis R. J. (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem., 270, 7420–7426.
Reunanen N., Westermarck J., Hakkinen L., Holmstrom T. H., Elo I., Eriksson J. E., and Kahari V. M. (1998) Enhancement of fibroblast collagenase (matrix metalloproteinase-1) gene expression by ceramide is mediated by extracellular signal-regulated and stress-activated protein kinase pathways. J. Biol. Chem. 273, 5137–5145.
Ridley S. H., Sarsfield S. J., Lee J. C., Bigg H. F., Cawston T. E., Taylor D. J., DeWitt D. L., and Saklatvala J. (1997) Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J. Immunol. 158, 3165–3173.
Darnell J. E., Jr. (1997) STATs and gene regulation, Science, 277, 1630–1635.
Korzus E., Nagase H., Rydell R., and Travis J. (1997) The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression. J. Biol. Chem. 272, 1188–1196.
Yu C. L., Meyer D. J., Campbell G. S., Larner A. C., Carter-Su C., Schwartz J., and Jove R. (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81–83.
Troppmair J., Bruder J. T., Munoz H., Lloyd P. A., Kyriakis J., Banerjee P., Avruch J., and Rapp U. R. (1994) Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. J. Biol. Chem. 269, 7030–7035.
Schlaepfer D. D. and Hunter T. (1997) Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J. Biol. Chem. 272, 13,189–91,315.
Daphna-Iken D., and Morrison A. R. (1995) Interleukin-1 beta induces interstitial collagenase gene expression and protein secretion in renal mesangial cells. Am. J. Physiol. 269, F831–F837.
Vincenti M. P., Coon C. I., White L. A., Barchowsky A., and Brinckerhoff C. E. (1996) Src-related tyrosine kinases regulate transcriptional activation of the interstitial collagenase gene, MMP-1, in interleukin-1-stimulated synovial fibroblasts. Arthritis Rheum. 39, 574–582.
Sudbeck B. D., Parks W. C., Welgus H. G., and Pentland A. P. (1994) Collagen-stimulated induction of keratinocyte collagenase is mediated via tyrosine kinase and protein kinase C activities. J. Biol. Chem. 269, 30,022–30,029.
Vincenti M. P., White L. A., Schroen D. J., Benbow U., and Brinckerhoff C. E. (1996) Regulating expression of the gene for matrix metalloproteinase-1 (collagenase): mechanisms that control enzyme activity, transcription, and mRNA stability. Crit. Rev. Euk. Gene Express. 6, 391–411.
Shlopov B. V., Lie W. R., Mainardi C. L., Cole A. A., Chubinskaya S., and Hasty K. A. (1997) Osteoarthritic lesions: involvement of three different collagenases. Arthritis Rheum. 40, 2065–2074.
Airola K., Johansson N., Kariniemi A. L., Kahari V. M., and Saarialho-Kere U. K. (1997) Human collagenase-3 is expressed in malignant squamous epithelium of the skin. J. Invest. Dermatol. 109, 225–231.
Johansson N., Airola K., Grenman R., Kariniemi A. L., Saarialho-Kere U., and Kahari V. M. (1997) Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am. J. Pathol. 151, 499–508.
Uria J. A., Stahle-Backdahl M., Seiki M., Fueyo A., and Lopez-Otin C. (1997) Regulation of collagenase-3 expression in human breast carcinomas is mediated by stromal-epithelial cell interactions. Cancer Res. 57, 4882–4888.
Johansson N., Saarialho-Kere U., Airola K., Herva R., Nissinen L., Westermarck J., Vuorio E., Heino J., and Kahari V. M. (1997) Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development. Developmental Dynamics 208, 387–397.
Stahle-Backdahl M., Sandstedt B., Bruce K., Lindahl A., Jimenez M. G., Vega J. A., and López-Otin C. (1997) Collagenase-3 (MMP-13) is expressed during human fetal ossification and re-expressed in postnatal bone remodeling and in rheumatoid arthritis. Lab. Invest, 76, 717–728.
Mitchell P. G., Magna H. A., Reeves L. M., Lopresti-Morrow L. L., Yocum S. A., Rosner P. J., Geoghegan K. F., and Hambor J. E. (1996) Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest. 97, 761–768.
Borden P., Solymar D., Sucharczuk A., Lindman B., Cannon P., and Heller R. A. (1996) Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes (published erratum appears in J Biol Chem 1996 Dec 27;271(52):33706). J. Biol. Chem. 271, 23,577–23,581.
Lindy O., Konttinen Y. T., Sorsa T., Ding Y., Santavirta S., Ceponis A., and Lopez-Otin C. (1997) Matrix metalloproteinase 13 (collagenase 3) in human rheumatoid synovium. Arthritis Rheum. 40, 1391–1399.
Vaalamo M., Mattila L., Johansson N., Kariniemi A. L., Karjalainen-Lindsberg M. L., Kahari V. M., and Saarialho-Kere U. (1997) Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J. Invest. Dermatol. 109, 96–101.
Saarialho-Kere U. K., Kovacs S. O., Pentland A. P., Olerud J. E., Welgus H. G., and Parks W. C. (1993) Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J. Clin. Invest. 92, 2858–2866.
Vogel W., Gish G. D., Alves F., and Pawson T. (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol. Cell 1, 13–23.
Nie D., Ishikawa Y., Yoshimori T., Wuthier R. E., and Wu L. N. (1998) Retinoic acid treatment elevates matrix metalloproteinase-2 protein and mRNA levels in avian growth plate chondrocyte cultures. J. Cell Biochem. 68, 90–99.
Fosang A. J., Last K., Knauper V., Murphy G., and Neame P. J. (1996) Degradation of cartilage aggrecan by collagenase-3 (MMP-13). FEBS Letters 380, 17–20.
Ballock R. T., Heydemann A., Wakefield L. M., Flanders K. C., Roberts A. B., and Sporn M. B. (1994) Inhibition of the chondrocyte phenotype by retinoic acid involves upregulation of metalloprotease genes independent of TGF-beta. J. Cell Phys. 159, 340–346.
Kelly W. N., Harris E. D., Ruddy S., and Sledge C. B. (1993) Textbook of Rheumatology. W.B. Saunders, Philadelphia.
Trentham D. E. and Brinckerhoff C. E. (1982) Augmentation of collagen arthritis by synthetic analogues of retinoic acid. J. Immunol. 129, 2668–2672.
Mauviel A., Chung K. Y., Agarwal A., Tamai K., and Uitto J. (1996) Cell-specific induction of distinct oncogenes of the Jun family is responsible for differential regulation of collagenase gene expression by transforming growth factor-beta in fibroblasts and keratinocytes. J. Biol. Chem. 271, 10,917–10,923.
Karin M. (1995) The Regulation of AP-1 Activity by Mitogen-activated Protein Kinases. Cell 270, 16,483–16,486.
Wilson C. L., Heppner K. J., Rudolph L. A., and Matrisian L. M. (1995) The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. Mol. Biol. Cell 6, 851–869.
Rodgers W. H., Osteen K. G., Matrisian L. M., Navre M., Giudice L. C., and Gorstein F. (1993) Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am. J. Ostet. Gynecol. 168, 253–260.
Woessner J. F., Jr. (1996) Regulation of matrilysin in the rat uterus. Biochem. Cell Biol. 74, 777–784.
Saarialho-Kere U. K., Crouch E. C., and Parks W. C. (1995) Matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. J. Invest. Dermatol. 105, 190–196.
Basset P., Bellocq J. P., Wolf C., Stoll I., Hutin P., Limacher J. M., Podhajcer O. L., Chenard M. P., Rio M. C., and Chambon P. (1990) A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348, 699–704.
McDonnell S., Navre M., Coffey R. J., Jr., and Matrisian L. M. (1991) Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. Mol. Carcinogen. 4, 527–533.
Muller D., Breathnach R., Engelmann A., Millon R., Bronner G., Flesch H., Dumont P., Eber M., and Abecassis J. (1991) Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. Int. J. Cancer 48, 550–556.
Karelina T. V., Goldberg G. I., and Eisen A. Z. (1994) Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J. Invest. Dermatol. 103, 482–487.
Powell W. C., Knox J. D., Navre M., Grogan T. M., Kittelson J., Nagle R. B., and Bowden G. T. (1993) Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunode-ficient mice. Cancer Res. 53, 417–422.
Witty J. P., McDonnell S., Newell K. J., Cannon P., Navre M., Tressler R. J., and Matrisian L. M. (1994) Modulation of matrilysin levels in colon carcinoma cell lines affects tumorigenicity in vivo. Cancer Res. 54, 4805–4812.
Shapiro S. D., Griffin G. L., Gilbert D. J., Jenkins N. A., Copeland N. G., Welgus H. G., Senior R. M., and Ley T. J. (1992) Molecular cloning, chromosomal localization, and bacterial expression of a murine macrophage metalloelastase. J. Biol. Chem. 267, 4664–4671.
Hautamaki R. D., Kobayashi D. K., Senior R. M., and Shapiro S. D. (1997) Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277, 2002–2004.
Shapiro S. D. (1994) Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am. J. Resp. & Crit. CareMed. 150, S160–164.
Shipley J. M., Wesselschmidt R. L., Kobayashi D. K., Ley T. J., and Shapiro S. D. (1996) Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Nat. Acad. Sci. USA 93, 3942–3946.
De Clerck Y. A., Shimada H., Taylor S. M., and Langley K. E. (1994) Matrix metalloproteinases and their inhibitors in tumor progression. Annals of the New York Academy of Sciences 732, 222–232.
Vincenti M. P., Clark I. M., and Brinckerhoff C. E. (1994) Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? (see comments). Arthritis Rheum. 37, 1115–1126.
Rasmussen H. S. and McCann P. P. (1997) Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat. Pharmacol. Therapeut. 75, 69–75.
Gross J. and Lapiere C. (1962) Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc. Natl. Acad. Sci. 48, 1014–1022.
Gross R. H., Sheldon L. A., Fletcher C. F., and Brinckerhoff C. E. (1984) Isolation of collagenase cDNA clone and measurement of changing collagenase mRNA levels during induction in rabbit synovial fibroblasts. Proc. Natl. Acad. Sci. USA 81, 1981–1985.
Goldberg G., Wilhelm S. M., A., K., Bauer E. A., Grant G. A., and Eisen A. Z. (1986) Human fibroblast collagenase: complete primary structure and homology to an oncogene transforation-induced rat protein. J. Biol. Chem. 261, 5645–5650.
Woessner J. F., Jr. (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. Faseb. J. 5, 2145–2154.
Nagase H. (1997) Activation Mechanisms of Matrix Metalloproteinases. Biol Chem. 378, 151–160.
Collier I. E., Bruns G. A., Goldberg G. I., and Gerhard D. S. (1991) On the structure and chromosome location of the 72-and 92-kDa human type IV collagenase genes. Genomics. 9, 429–434.
Matrisian L. M., Leroy P., Ruhlmann C., Gesnel M. C., and Breathnach R. (1986) Isolation of the oncogene and epidermal growth factor-induced transin gene: complex control in rat fibroblasts. Mol. Cell Biol. 6, 1679–1686.
Sanchez-Lopez R., Nicholson R., Gesnel M. C., Matrisian L. M., and Breathnach R. (1988) Structure-function relationships in the collagenase family member transin. J. Biol. Chem. 263, 11,892–11,899.
Muller D., Quantin B., Gesnel M. C., Millon-Collard R., Abecassis J., and Breathnach R. (1988) The collagenase gene family in humans consists of at least four members. Biochem. J. 253, 187–192.
Quantin B., Murphy G., and Breathnach R. (1989) Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. Biochem. 28, 5327–5334.
Hasty K. A., Pourmotabbed T. F., Goldberg G. I., Thompson J. P., Spinella D. G., Stevens R. M., and Mainardi C. L. (1990) Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J. Biol. Chem. 265, 11,421–11,424.
Wilhelm S. M., Collier I. E., Marmer B. L., Eisen A. Z., Grant G. A., and Goldberg G. I. (1989) SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages (published erratum appears in J. Biol. Chem. 1990 Dec 25;265(36):22570). J. Biol. Chem. 264, 17,213–17,221.
Masure S., Nys G., Fiten P., Van Damme J., and Opdenakker G. (1993) Mouse gelatinase B. cDNA cloning, regulation of expression and glycosylation in WEHI-3 macrophages and gene organisation. Eur. J. Biochem. 218, 129–141.
Breathnach R., Matrisian L. M., Gesnel M. C., Staub A., and Leroy P. (1987) Sequences coding for part of oncogene-induced transin are highly conserved in a related rat gene, Nucleic Acids Res. 15, 1139–1151.
168.-Quinn C. O., Scott D. K., Brinckerhoff C. E., Matrisian L. M., Jeffrey J. J., and Partridge N. C. (1990) Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells. J. Biol. Chem. 265, 22,342–2237.
Pendas A. M., Matilla T., Estivill X., and LĂłpez-OtĂn C. (1995) The human collagenase-3 (CLG3) gene is located on chromosome 1 1q22.3 clustered to other members of the matrix metalloproteinase gene family. Genomics 26, 615–618.
Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M. (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells (see comments). Nature 370, 61–65.
Will H. and Hinzmann B. (1995) cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment. Eur. J. Biochem. 231, 602–608.
Takino T., Sato H., Shinagawa A., and Seiki M. (1995) Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family. J. Biol. Chem. 270, 23,013–23,020.
Puente X. S., Pendas A. M., Llano E., Velasco G., and LĂłpez-OtĂn C. (1996) Molecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma. Cancer Res. 56, 944–949.
Stolow M. A., Bauzon D. D., Li J., Sedgwick T., Liang V. C., Sang Q. A., and Shi Y. B. (1996) Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development. Mol. Biol. Cell 7, 1471–1483.
Yang M., Murray M. T., and Kurkinen M. (1997) A novel matrix metalloproteinase gene (XMMP) encoding vitronectin-like motifs is transiently expressed in Xenopus laevis early embryo development. J. Biol. Chem. 272, 13,527–13,533.
Cossins J., Dudgeon T. J., Catlin G., Gearing A. J., and Clements J. M. (1996) Identification of MMP-18, a putative novel human matrix metalloproteinase. Biochem. Biophys. Res. Com. 228, 494–498.
Pendas A. M., Knauper V., Puente X. S., Llano E., Mattei M. G., Apte S., Murphy G., and Lopez-Otin C. (1997) Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J. Biol. Chem. 272, 4281–4286.
Llano E., Pendas A. M., Knauper V., Sorsa T., Salo T., Salido E., Murphy G., Simmer J. P., Bartlett J. D., and Lopez-Otin C. (1997) Identification and structural and functional characterization of human enamelysin (MMP-20). Biochem. 36, 15,101–15,118.
Docherty A. J., Lyons A., Smith B. J., Wright E. M., Stephens P. E., Harris T. J., Murphy G., and Reynolds J. J. (1985) Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318, 66–69.
Goldberg G. I., Strongin A., Collier I. E., Genrich L. T., and Marmer B. L. (1992) Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J. Biol. Chem. 267, 4583–4591.
Gomez D. E., Alonso D. F., Yoshiji H., and Thorgeirsson U. P. (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur. J. Cell Biol. 74, 111–122.
Stetler-Stevenson W. G., Krutzsch H. C., and Liotta L. A. (1989) Tissue inhibitor sof metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. J. Biol. Chem. 264, 17,374–17,378.
Goldberg G. I., Marmer B. L., Grant G. A., Eisen A. Z., Wilhelm S., and He C. S. (1989) Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. Proc. Nat. Acad. Sci. USA 86, 8207–8211.
Zucker S., Drews M., Conner C., Foda H. D., DeClerck Y. A., Langley K. E., Bahou W. F., Docherty A. J., and Cao J. (1998) Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J. Biol. Chem. 273, 1216–1222.
Apte S. S., Mattei M. G., and Olsen B. R. (1994) Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 19, 86–90.
Apte S. S., Olsen B. R., and Murphy G. (1995) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family (published erratum appears in J Biol Chem 1996 Feb 2;271(5):2874). J. Biol. Chem. 270, 14,313–14,318.
Apte S. S., Hayashi K., Seldin M. F., Mattei M. G., Hayashi M., and Olsen B. R. (1994) Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10. Developmental Dynamics. 200, 177–197.
Apte S. S., Olsen B. R., and Murphy G. (1996) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J. Biol. Chem. 271, 2874.
Greene J., Wang M., Liu Y. E., Raymond L. A., Rosen C., and Shi Y. E. (1996) Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J. Biol. Chem. 271, 30,375–30,380.
Leco K. J., Apte S. S., Taniguchi G. T., Hawkes S. P., Khokha R., Schultz G. A., and Edwards D. R. (1997) Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Letters 401, 213–217.
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Vincenti, M.P. (2001). The Matrix Metalloproteinase (MMP) and Tissue Inhibitor of Metalloproteinase (TIMP) Genes. In: Clark, I.M. (eds) Matrix Metalloproteinase Protocols. Methods in Molecular Biology™, vol 151. Humana Press. https://doi.org/10.1385/1-59259-046-2:121
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