Transforming growth factor β inhibitory element in the rabbit matrix metalloproteinase-1 (collagenase-1) gene functions as a repressor of constitutive transcription

White, Lori A.; Mitchell, Teresa; Brinckerhoff, Constance E.

doi:10.1016/s0167-4781(00)00002-6

Cited by 87 publications

(78 citation statements)

References 22 publications

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“…17 Moreover, earlier studies have demonstrated that TGFb plays a regulatory role in gene transcription, and some genes comprise TGFb inhibitory elements (TIE). 27,28 Our experiments establish the presence of TIE in the LEDGF promoter. 29 TGFb inhibits the gene transcription of LEDGF.…”

Section: Introductionsupporting

confidence: 54%

“…As mentioned above, LEDGF promoter bears TIE, a target for transcriptional repression of LEDGF by TGFb. 29 A CAT assay using the LEDGF promoter containing TIE [27][28][29] is activated in the presence of PRDX6, suggesting that the PRDX6 disrupts harmful ROS-mediated TGFb1 signaling. In addition, the expression levels of aB-crystallin are recovered (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

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Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

et al. 2005

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PRDX6, a member of the peroxiredoxins (PRDXs) family, is a key player in the removal of reactive oxygen species (ROS). Using targeted inactivation of the Prdx6 gene, we present evidence that the corresponding protein offsets the deleterious effects of ROS on lens epithelial cells (LECs) and regulates gene expression by limiting its levels. PRDX6-depleted LECs displayed phenotypic alterations and elevated a-smooth muscle actin and big-h3 expression (markers for cataractogenesis), indistinguishable from transforming growth factor b (TGFb)-induced changes. Biochemical assays disclosed enhanced levels of ROS, as well as high expression and activation of TGFb1 in Prdx6 À/À LECs. A CAT assay revealed transcriptional repression of lens epithelium-derived growth factor (LEDGF), HSP27, and aB-crystallin promoter activities in these cells. A gel mobility shift assay demonstrated the attenuation of LEDGF binding to heat shock or stress response elements present in these genes. A supply of PRDX6 toPrdx6 À/À LECs reversed these changes. Based on the above data, we propose a rheostat role for PRDX6 in regulating gene expression by controlling the ROS level to maintain cellular homeostasis.

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Section: Introductionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

et al. 2005

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“…In other cases, TGF-␤ 1 signaling results in an inhibition of inducible gene expression. For example, TGF-␤ 1 antagonizes phorbol estermediated transcriptional induction of matrix metalloproteinase-1 through a TGF-␤ inhibitory element (24). In intestinal epithelial cells, TGF-␤ 1 attenuates glucocorticoid-mediated induction of haptoglobin mRNA by inhibiting CAAT/enhancerbinding protein binding to the proximal promoter (25).…”

Section: Tgf-␤ 1 -Mediated Down-regulation Of the Flk-1/kdr Promoter mentioning

confidence: 99%

Transforming Growth Factor-β1-mediated Inhibition of the flk-1/KDR Gene Is Mediated by a 5′-Untranslated Region Palindromic GATA Site

Minami¹,

Rosenberg²,

Aird³

2001

Journal of Biological Chemistry

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The angiogenic effects of vascular endothelial growth factor are mediated predominantly by the FLK-1/KDR receptor. An understanding of the transcriptional control mechanisms underlying flk-1/KDR expression should provide insight into the molecular basis of angiogenesis. In this study, we show that transforming growth factor-␤ 1 (TGF-␤ 1 ) down-regulates expression of the endogenous flk-1/KDR gene in endothelial cells. In transient transfection assays, this effect was mapped to a palindromic GATA site in the 5-untranslated region. In electrophoretic mobility shift assays, the palindromic GATA site was shown to bind to two molecules of GATA protein. Moreover, DNA-GATA interactions were inhibited by TGF-␤ 1 . Finally, in cotransfection assays, transactivation of the flk-1/KDR promoter by GATA-1 or GATA-2 was attenuated in TGF-␤ 1 -treated cells. Taken together, these results suggest that the TGF-␤-1-mediated inhibition of the flk-1/KDR gene is mediated by a 5-untranslated region palindromic GATA site. Vascular endothelial growth factor (VEGF)1 is an important regulator of new blood vessel formation in both health and disease states. The effects of VEGF are mediated by two high affinity transmembrane receptors, FLK-1/KDR and FLT-1 (1). Of these two receptors, FLK-1/KDR appears to play a more prominent role in VEGF-mediated signaling. FLK-1/KDR is a membrane-bound receptor of the tyrosine kinase family that is expressed exclusively in endothelial cells. The FLK-1/KDR receptor is expressed early in the mouse embryo, where it is believed to play an important role in endothelial cell differentiation and vasculogenesis (2). In the adult, FLK-1/KDR expression is down-regulated (3). However, the gene may be reactivated and/or up-regulated in tumor vascular beds or in the setting of cardiac angiogenesis (4) and proliferative retinopathies (5, 6). In addition, FLK-1/KDR may serve an important role in wound healing and bone remodeling (7).An understanding of the mechanisms that underlie the transcriptional regulation of the flk-1/KDR gene might provide important information about the molecular basis of endothelial cell differentiation and angiogenesis. The human and mouse flk-1/KDR promoters have been sequenced and characterized (8 -12). Under in vitro conditions, the 5Ј-flanking region and first exon have been shown to contain information for endothelial cell-specific expression, whereas in transgenic mouse assays, intronic enhancer sequences play a critical role in mediating expression within the vasculature (13).Although the above studies provide insight into the mechanisms of endothelial cell-specific gene regulation, they do not address the question of how the flk-1/KDR promoter is temporally controlled by positive and negative regulators of angiogenesis. Transforming growth factor-␤ 1 (TGF-␤ 1 ) has a biphasic effect on basic fibroblast growth factor-and VEGF-induced angiogenesis in vitro (14). At low concentrations TGF-␤ 1 enhances endothelial cell response, whereas at high concentrations, TGF-␤ 1 inhibits the effects ...

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“…For instance, inflammation-induced expression of nitric oxide synthetase, E-selectin, MMP-1, and MMP-3 are abrogated in cell type-specific manner by TGF-␤ (24 -28). Repression of MMP-1 transcription by TGF-␤ in rabbit synovial fibroblasts was shown to be mediated through a sequence at Ϫ246 bp of the promoter that resembled a TGF-␤ inhibitory element previously identified in the rat stromelysin gene promoter (29). However, the level and mechanisms underlying the antagonistic regulation of MMP-1 expression by IL-1␤ and TGF-␤ remain uncertain.…”

mentioning

confidence: 93%

Transforming Growth Factor-β Repression of Matrix Metalloproteinase-1 in Dermal Fibroblasts Involves Smad3

Yuan¹,

Varga²

2001

Journal of Biological Chemistry

243

156

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Transforming growth factor β inhibitory element in the rabbit matrix metalloproteinase-1 (collagenase-1) gene functions as a repressor of constitutive transcription

Cited by 87 publications

References 22 publications

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

Transforming Growth Factor-β1-mediated Inhibition of the flk-1/KDR Gene Is Mediated by a 5′-Untranslated Region Palindromic GATA Site

Transforming Growth Factor-β Repression of Matrix Metalloproteinase-1 in Dermal Fibroblasts Involves Smad3

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