Independent regulation of matrix metalloproteinases and plasminogen activators in human fibrosarcoma cells

Lim, Yooseong; Sugiura, Yasuo; Laug, Walter E.; Sun, Bo; Garcia, A.Minerva; DeClerck, Yves A.

doi:10.1002/(sici)1097-4652(199605)167:2<333::aid-jcp18>3.0.co;2-8

Cited by 34 publications

(15 citation statements)

References 43 publications

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“…Unlike TPA, GI129471 did not induce nor increase MMP-1, MT1-MMP, or TIMP-1 mRNA levels (data not shown). Our data are consistent with earlier reports demonstrating the upregulating activity of TPA on MMP-1, MMP-3, MMP-9, MT1-MMP, and TIMP-1 expression in different cell types [46,47,51].…”

Section: Gi129471 Increases Mmp-9 Mrna Steady-state Level In Ht 1080 supporting

confidence: 94%

“…2A). TPA also induced the production of a 45-kDa protein with a weak gelatinolytic activity corresponding to MMP-1 [46], and increased the amount of 62 and 59-kDa active MMP-2 forms, accounting for the well-documented stimulatory effect of TPA on the MT1-MMP-dependent maturation process of pro-MMP-2 [25,46,47]. Similarly to TPA, treatment of the cells with GI129471 dose dependently stimulated the secretion of pro-MMP-9 with a maximal 6.6-fold stimulation after 48 h and 1 µM GI129471 (Fig.…”

Section: Mmp-9 Secretion By Ht1080 Is Stimulated By Gi129471mentioning

confidence: 98%

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Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Maquoi

Munaut

Colige

et al. 2002

Experimental Cell Research

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Enhanced expression and activation of matrix met-alloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with β-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as 11-1β and TNF-α were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-Spectrum MMPIs.

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Section: Gi129471 Increases Mmp-9 Mrna Steady-state Level In Ht 1080 supporting

confidence: 94%

Section: Mmp-9 Secretion By Ht1080 Is Stimulated By Gi129471mentioning

confidence: 98%

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Maquoi

Munaut

Colige

et al. 2002

Experimental Cell Research

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“…As previously reported by others [6,13,15,[56][57][58], we showed that TPA-or ConA-treated HT1080 cells increased MT1-MMP mRNA expression and substantially upregulated MT1-MMP protein synthesis. Furthermore, both treatments induced the formation of a 43-kDa MT1-MMP species (Figs.…”

Section: Mmp-2 Activation By Tpa-and Cona-treated Ht1080 Cellssupporting

confidence: 90%

Type IV Collagen Induces Matrix Metalloproteinase 2 Activation in HT1080 Fibrosarcoma Cells

Maquoi

Frankenne

Noël

et al. 2000

Experimental Cell Research

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Matrix metalloproteinase 2 (MMP-2) activation has been described as a "master switch" which triggers tumor spread and metastatic progression. We show here that type IV collagen, a major component of basement membranes, promotes MMP-2 activation by HT1080 cells. When plated on plastic, HT1080 cells constitutively processed the 66-kDa pro-MMP-2 into a 62-kDa intermediate activated form, most probably through a membrane type (MT) 1 MMP-dependent mechanism. In the presence of type IV collagen, part of this intermediate form was further processed to fully activated 59-kDa MMP-2. This activation was prevented by tissue inhibitor of MMP (TIMP)-2 and a broad-spectrum hydroxamic acid-based synthetic MMP inhibitor (GI129471). Type IV collagen-mediated pro-MMP-2 activation did not involve either a transcriptional modulation of MMP-2, MT1-MMP, or TIMP-2 expression nor any alteration of MT1-MMP protein synthesis or processing. An inverse relationship between MMP-2 activation and the concentration of secreted TIMP-2 was observed. This is consistent with our previous report that TIMP-2 degradation is probably linked to the MT1-MMP-dependent MMP-2 activation mechanism. Because invasive tumor cells must breach basement membranes at different steps of the metastatic dissemination, the ability of HT1080 cells to activate pro-MMP-2 in the presence of type IV collagen might represent a key regulatory mechanism for the acquisition of an invasive potential.

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“…TIMP and MMP Analysis in Culture Medium-Analysis of MMP expression in serum-free culture medium of cell lines was performed using SDS-polyacrylamide gel zymography as described previously (21). When needed, samples were concentrated by ultrafiltration using Microcon filters (Amicon, Beverly, MA; molecular weight cutoff, 10,000).…”

Section: Methodsmentioning

confidence: 99%

NF-Y and Sp1 Cooperate for the Transcriptional Activation and cAMP Response of Human Tissue Inhibitor of Metalloproteinases-2

Zhong¹,

Hammani²,

Bae³

et al. 2000

Journal of Biological Chemistry

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The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) is a key determinant in the homeostasis of the extracellular matrix. We have identified two cis-acting elements involved in the transcriptional regulation of TIMP-2. The first is an inverted CCAAT box located at position ؊73 to ؊69 in the TIMP-2 promoter that binds the transcription factor NF-Y. The second is a GAGGAGGGGG motif located at position ؊107 to ؊98, that binds the transcription factors Sp1 and Sp3. NF-Y and Sp1 cooperate for the basal transcription activity of the promoter. We then determined that TIMP-2 is transcriptionally up-regulated by cAMP analogs. Up-regulation of TIMP-2 by dibutyryl cAMP is a delayed response that requires de novo protein synthesis and does not affect RNA stability. The NF-Y and the Sp1 binding site are both involved in cAMPdependent up-regulation of TIMP-2. Whereas NF-Y is essential for cAMP mediated regulation, Sp1 alone is not sufficient but enhances the activity of NF-Y. Dibutyryl cAMP has no effect on the expression of MMP-2 and MMP-9 and switches the MMP-TIMP balance in favor of the inhibitor.Tissue inhibitors of metalloproteinases (TIMPs) 1 are natural inhibitors of matrix metalloproteinases (MMPs), a family of proteases that degrade proteins of the extracellular matrix (ECM) (1). These inhibitors play an important role in the control of the homeostasis of the ECM under conditions that are associated with intense connective tissue remodeling such as implantation, embryogenesis, organogenesis, wound repair, arthritis, and cancer invasion (2, 3). Four members of the TIMP family, designated TIMP-1 to TIMP-4, have been identified so far in many species including human (4 -8). These inhibitors differ in many aspects such as tissue-specific expression, solubility, and regulation but share a common antiprotease function because of their ability to form stable enzyme-inhibitor complexes with all members of the MMP family. The balance between MMPs and TIMPs is a key element that controls the turnover of the ECM and is itself under the influence of a large variety of growth factors and cytokines that transcriptionally regulate MMP and TIMP expression. Whereas some of these factors such as transforming growth factor ␤ have a coordinated effect that decreases ECM degradation by up-regulating TIMP and down-regulating MMP expression (9, 10), other factors such as interleukin-1, interleukin-6, or oncostatin M have a much less predictable effect on the ECM because they simultaneously up-or down-regulate MMP and TIMP expression (11)(12)(13)(14).The molecular basis for the transcriptional regulation of MMP and TIMP expression has been investigated, and several cis-acting elements in the promoter of many MMPs and TIMPs responsible for transcription control have been identified. In particular, a PEA-3 motif and an AP-1 motif located in close proximity in the promoter of many MMPs and TIMPs have been shown to mediate their enhanced expression by phorbol esters and serum factors (15), and a transform...

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Independent regulation of matrix metalloproteinases and plasminogen activators in human fibrosarcoma cells

Cited by 34 publications

References 43 publications

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Type IV Collagen Induces Matrix Metalloproteinase 2 Activation in HT1080 Fibrosarcoma Cells

NF-Y and Sp1 Cooperate for the Transcriptional Activation and cAMP Response of Human Tissue Inhibitor of Metalloproteinases-2

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