Control of the Tissue Inhibitor of Metalloproteinases–1 Promoter in Culture–Activated Rat Hepatic Stellate Cells: Regulation by Activator Protein–1 Dna Binding Proteins

Bahr, Matthias J.; Vincent, Karen J.; Arthur, Michael J. P.; Fowler, Andrew; Smart, David E.; Wright, Matthew C.; Clark, Ian M.; Benyon, R. Christopher; Iredale, John P.; Mann, Derek A.

doi:10.1002/hep.510290333

Cited by 78 publications

(105 citation statements)

References 33 publications

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“…Although TIMP-1 promoter contains activator protein-1 binding site (31), inhibition of activator protein-1 does not always lead to TIMP-1 down-regulation. For example, in hepatic stellate cells, induction of c-Fos and c-Jun is unlikely to result in transactivation of the TIMP-1 promoter (32). Therefore, it is suggested that unidentified factors may be involved in the regulation of TIMP-1 expression (32 -34).…”

Section: Discussionmentioning

confidence: 99%

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

Yoon

Shin

Lee³

et al. 2006

Molecular Cancer Therapeutics

105

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Matrix metalloproteinase (MMP)-9 plays a key role in tumor invasion. Inhibitors of MMP-9 were screened from Metasequoia glyptostroboides (Dawn redwood) and one potent inhibitor, isoginkgetin, a biflavonoid, was identified. Noncytotoxic levels of isoginkgetin decreased MMP-9 production profoundly, but up-regulated the level of tissue inhibitor of metalloproteinase (TIMP)-1, an inhibitor of MMP-9, in HT1080 human fibrosarcoma cells. The major mechanism of Ras-dependent MMP-9 production in HT1080 cells was phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor-KB (NF-KB) activation. Expression of dominant-active H-Ras and p85 (a subunit of PI3K) increased MMP-9 activity, whereas dominant-negative forms of these molecules decreased the level of MMP-9. H-Ras did not increase MMP-9 in the presence of a PI3K inhibitor, LY294002, and a NF-KB inhibitor, SN50. Further studies showed that isoginkgetin regulated MMP-9 production via PI3K/Akt/NF-KB pathway, as evidenced by the findings that isoginkgetin inhibited activities of both Akt and NF-KB. PI3K/Akt is a well-known key pathway for cell invasion, and isoginkgetin inhibited HT1080 tumor cell invasion substantially. Isoginkgetin was also quite effective in inhibiting the activities of Akt and MMP-9 in MDA-MB-231 breast carcinomas and B16F10 melanoma. Moreover, isoginkgetin treatment resulted in marked decrease in invasion of these cells. In summary, PI3K/ Akt is a major pathway for MMP-9 expression and isoginkgetin markedly decreased MMP-9 expression and invasion through inhibition of this pathway. This suggests that isoginkgetin could be a potential candidate as a therapeutic agent against tumor invasion. [Mol Cancer Ther 2006;5(11):2666 -75]

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Section: Discussionmentioning

confidence: 99%

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

Yoon

Shin

Lee³

et al. 2006

Molecular Cancer Therapeutics

105

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“…Primary rodent HSCs were isolated and maintained as previously described. [3][4][5][6][7] The LX-2 line was described elsewhere. 7 (L)-JNKI1, a cell-permeable peptide inhibitor of JNKs, SP600125 SAPK inhibitor II, and MAPKK inhibitor PD98059 were purchased from Calbiochem.…”

Section: Isolation and Culture Of Quiescent And Activatedmentioning

confidence: 99%

mentioning

confidence: 99%

“…3 TIMP-1 gene transcription is induced during culture activation of isolated HSCs and is under the control of regulatory elements in the TIMP-1 promoter including activator protein-1 (AP-1) and RUNX binding sites. [4][5][6][7] The AP-1 site is perfectly conserved in human and rodent TIMP-1 genes 8 and binds homo-or heterodimers of Jun proteins and their Fos/ATF partners. 9 Of the three Jun proteins (JunB, c-Jun, and JunD), JunD is the protein predominantly expressed in activated HSCs.…”

mentioning

confidence: 99%

“…9 Of the three Jun proteins (JunB, c-Jun, and JunD), JunD is the protein predominantly expressed in activated HSCs. 4,6 Homodimeric JunD is the optimal AP-1 regulator of TIMP-1 gene transcription in HSCs. 6 JunD also regulates IL-6 and MMP-9 transcription in HSCs, indicating it may be a key profibrogenic regulator.…”

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confidence: 99%

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JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation

et al. 2006

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A ctivated (or myofibroblastic) hepatic stellate cells (HSCs) are cellular mediators of liver fibrosis through their secretion of interstitial collagens and tissue inhibitor of metalloproteinase-1 (TIMP-1), 1,2 which is a broad specific inhibitor of the matrix metalloproteinases (MMPs) and prevents MMP-catalyzed degradation of interstitial collagens in order to promote collagen deposition. A second fibrogenic role identified for TIMP-1 is as a suppressor of HSC apoptosis. 3 TIMP-1 gene transcription is induced during culture activation of isolated HSCs and is under the control of regulatory elements in the TIMP-1 promoter including activator protein-1 (AP-1) and RUNX binding sites. [4][5][6][7]

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Alterations in the gene expression profile of MCF-7 breast tumor cells in response to c-Jun

et al. 2000

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MCF7 breast tumor cells overexpressing human c‐Jun exhibit a transformed phenotype characterized not only by increased tumorigenicity but also by enhanced motility and invasion. The cellular phenotypic response to c‐Jun overexpression is likely due, at least in part, to altered patterns of gene expression. In order to begin to understand the complexities by which elevated production of c‐Jun alters the state of the cell, we have profiled the expression of 588 different genes by comparative hybridization. By using this approach, we have identified a total of 21 upregulated or downregulated gene targets responsive to c‐Jun overexpression. Interestingly, 8 of these genes have been previously found associated with c‐Jun or AP‐1 activity and therefore provide internal validation for this approach to target gene discovery. The remaining 13 genes represent potential new c‐Jun regulated target genes. Genomic sequence information was available for 15 of the 21 genes identified in this screen. Analysis of these genomic sequences revealed the presence of AP‐1 or AP‐1‐like sequences in 12 of the 15 genes examined. Consistent with a direct mechanism of target regulation by c‐Jun, gel shift analysis of selected AP‐1‐containing promoter regions revealed elevated and specific binding by proteins present in nuclear extracts of c‐Jun expressing MCF7 cells. Int. J. Cancer 88:180–190, 2000. © 2000 Wiley‐Liss, Inc.

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Control of the Tissue Inhibitor of Metalloproteinases–1 Promoter in Culture–Activated Rat Hepatic Stellate Cells: Regulation by Activator Protein–1 Dna Binding Proteins

Cited by 78 publications

References 33 publications

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt–dependent matrix metalloproteinase-9 expression

JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation

Alterations in the gene expression profile of MCF-7 breast tumor cells in response to c-Jun

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