RECK Negatively Regulates Matrix Metalloproteinase-9 Transcription

Takagi, Satoshi; Simizu, Siro; Osada, Hiroyuki

doi:10.1158/0008-5472.can-08-2635

Cited by 92 publications

(73 citation statements)

References 37 publications

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“…Knockdown of Fra-1, using siRNA in both BEAS-2B and primary HBE cells, resulted in a significant reduction in Fra-1 AP-1 DNA binding and MMP-9 protein expression in both BEAS-2B and primary HBE cells; this indicates that Fra-1 is necessary for MMP-9 transcription. These data are consistent with previous reports examining MMP-9 expression in response to different stimuli in different cell types (23,30,39,40). Using MEK inhibitors, we have established that activation of MEK1/2 is necessary for Fra-1 expression and HRVinduced MMP-9 expression.…”

Section: Discussionsupporting

confidence: 92%

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Tacon

Newton

Leigh

2012

The Journal of Immunology

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Matrix metalloproteinase-9 is implicated in airway inflammation and airway remodeling in asthma. We have previously confirmed that human rhinovirus-16 (HRV-16) infection increases MMP-9 expression both in vivo and in vitro. However, the role of the AP-1 sites within the MMP-9 promoter and the effect of commonly used asthma pharmacotherapies in modulating human rhinovirus (HRV)-induced MMP-9 production have not yet been elucidated. Experiments were performed in vitro in the human bronchial epithelial (HBE) cell line BEAS-2B and in primary HBE cells obtained from non-transplanted lungs. Using site-directed mutagenesis approaches, AP-1 sites were found to be necessary for HRV-induced MMP-9 promoter drive. EMSAs and supershift assays identified complexes consisting of Fos-related Ag-1 (Fra-1) in addition to other AP-1 subunits. Small interfering RNA approaches indicated that Fra-1 was induced upon HRV-16 infection in BEAS-2B cells and was necessary for MMP-9 expression in both BEAS-2B and primary HBE cells. Inhibition of MEK1/2 activity using PD98059 and U0126 reduced Fra-1 expression, DNA binding, MMP-9 promoter drive, and MMP-9 protein production. The long-acting β2-agonist formoterol and the glucocorticoid dexamethasone significantly reduced HRV-induced ERK phosphorylation, Fra-1, and MMP-9 expression in BEAS-2B cells. These data indicate that HRV-induced activation of the MEK/ERK MAPK pathway and Fra-1 expression are necessary for the upregulation of MMP-9 and can be modulated by two distinct but commonly used asthma pharmacotherapies. Together, these results offer insights into the mechanisms by which long-acting β2-agonists and glucocorticoids might reduce HRV-related asthma exacerbations.

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Section: Discussionsupporting

confidence: 92%

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Tacon

Newton

Leigh

2012

The Journal of Immunology

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“…2 and 3) are consistent with the model that RECK plays an important role in DSFmediated metastasis suppression. Our preliminary data indicate that RECK-depletion with siRNA suppresses DSF-mediated pro-MMP-9 down-regulation (data not shown), and this is consistent with the previous observation by Takagi et al that RECK suppresses MMP9 transcription [20]. It remains to be clarified, however, to what extent the up-regulated RECK contributes to the DSF-mediated metastasis suppression in vivo.…”

Section: Discussionsupporting

confidence: 92%

“…Expression of RECK in HT1080 cells results in down-regulation of pro-MMP-9 and active MMP-2 in culture supernatant [7,9,20] and in suppression of metastatic activity in nude mice [7]. To facilitate the evaluation of anti-tumorigenic/anti-metastatic activity of Reck-activating drugs in vivo, we established a luciferasetagged derivative of HT1080 (named RM72) that shows spontaneous lung-metastasis within two weeks after subcutaneous inoculation into nude mice.…”

Section: Effects Of Dsf On Tumor Growth and Metastasismentioning

confidence: 99%

A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs

et al. 2010

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AbstrAct:The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS 12V oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.

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“…It was demonstrated that MMP-9 is transcriptionally regulated by RECK by transcription factors Fra-1 and c-Jun through 12-O-tetradecanoylphorbol-13-acetateresponsive-1 site in the MMP-9 promoter (Takagi et al, 2009). Fra-1 and c-Jun are highly established downstream targets of EGFR signaling, and MMP-9 is indeed upregulated by EGF (Lyons et al, 1993).…”

Section: Reck Antagonizes Ras Signaling S Kitajima Et Almentioning

confidence: 99%

Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling

et al. 2010

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The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19Arf , Trp53 and p21 Cdkn1a. In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19 Arf , Trp53, p21Cdkn1a and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.

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RECK Negatively Regulates Matrix Metalloproteinase-9 Transcription

Cited by 92 publications

References 37 publications

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs

Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling

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