A Forkhead/Winged Helix-related Transcription Factor Mediates Insulin-increased Plasminogen Activator Inhibitor-1 Gene Transcription

Vulin, Anthony I.; Stanley, Frederick

doi:10.1074/jbc.m112073200

Cited by 22 publications

(23 citation statements)

References 59 publications

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“…Additively-The high levels of circulating PAI-1 found in diabetics could result from insulin stimulation of PAI-1 production as suggested previously (2,14). High levels of oxidative stress associated with diabetes might also contribute to maintenance of high PAI-1 (29).…”

Section: Insulin and Oxidative Stress Activate The Pai-1 Promotermentioning

confidence: 83%

“…We previously demonstrated that insulin activated the PAI-1 promoter through a forkhead-related response element (TTATTT) at Ϫ52/Ϫ43 of the PAI-1 promoter (14). Insulinincreased PAI-1 gene expression was inhibited by the expression of the DNA binding domain of forkhead.…”

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confidence: 99%

“…Chloramphenicol acetyltransferase (CAT) reporter plasmids were constructed from p800neo-Luc by PCR as previously described (22). Deletion mutants of this plasmid were made by PCR and point mutations of these plasmids were also made by PCR using mutant primers as described (14,23). The human insulin expression vector, pRT3HIR2, was the gift of Dr. J. Whittaker (Hagedorn Institute, Copenhagen, Denmark).…”

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confidence: 99%

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Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

Vulin

Stanley

2004

Journal of Biological Chemistry

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Oxidative stress is one of the characteristics of diabetes and is thought to be responsible for many of the pathophysiological changes caused by the disease. We previously identified an insulin response element in the promoter of plasminogen activator inhibitor 1 (PAI-1) that was activated by an unidentified member of the forkhead/winged helix (Fox) family of transcription factors. This element mediated a 5-7-fold increase in PAI-1 transcription because of insulin. Here we report that oxidative stress also caused a 3-fold increase in PAI-1 transcription and that the effect was additive with that of insulin. Antioxidants prevent this response. Mutational analysis of the PAI-1 promoter revealed that oxidative stress acted at an AP-1 site at ؊60/52 of the promoter. Gel mobility shift analysis demonstrated that binding to an AP-1 oligonucleotide was increased 4-fold by oxidative stress. Jun levels were increased by oxidants as assessed by reverse transcriptase-PCR. Western blotting demonstrated that a rapid and prolonged nuclear accumulation of phospho-c-Jun followed oxidant stimulation. The nuclear c-Jun phosphorylation was not observed in cells treated with reduced glutathione. Finally, JNK/SAPK activity was found to increase in response to oxidants, and inhibition of JNK/SAP blocked TBHQ-increased PAI-1-luciferase expression. Thus, oxidative stress stimulated AP-1 and activated the PAI-1 promoter.

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Section: Insulin and Oxidative Stress Activate The Pai-1 Promotermentioning

confidence: 83%

mentioning

confidence: 99%

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confidence: 99%

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Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

Vulin

Stanley

2004

Journal of Biological Chemistry

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“…PAI-1 gene transcription is positively regulated by various transcription factors, including Sp1 (12,36), Forkhead (61), and the hypoxia-inducible factor (27). Interestingly, an Sp1 and PAI-1 regulator, transforming growth factor ␤ (16, 18), is overexpressed at the mRNA level in Net mutant cells (Table 1), raising the possibility that it may contribute to the increase of PAI-1.…”

Section: Discussionmentioning

confidence: 99%

The Ternary Complex Factor Net Regulates Cell Migration through Inhibition of PAI-1 Expression

Buchwalter

Groß

Wasylyk

2005

Molecular and Cellular Biology

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Net, Elk-1, and Sap-1 are members of the ternary complex factor (TCF) subfamily of Ets transcription factors. They form ternary complexes with serum response factor (SRF) on serum response elements of immediate early genes such as c-fos and egr-1 and mediate responses to growth factors and mitogen-activated protein kinase signaling. Although the TCFs have been extensively studied as intermediates in signaling cascades, surprisingly little is known about their different target genes and physiological functions. We report that Net homozygous mutant mouse embryonic fibroblasts have a defect in cell migration. This defect results at least in part from increased expression of plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor (serpin) that controls extracellular proteolysis and cell matrix adhesion. The defect in cell migration can be reverted by the addition of a PAI-1 blocking antibody. Net represses PAI-1 promoter activity and binds to a specific region of the promoter containing Ets binding sites in the absence of SRF. We conclude that Net is a negative regulator of PAI-1 expression and is thereby involved in cell migration.The three ternary complex factors (TCFs) Net (also called Elk-3, SAP-2, and ERP), Elk-1, and Sap-1 have become paradigms in the understanding of signal transduction and transcription regulation, and there is great current interest in establishing their physiological functions (for reviews, see references 8, 20, 48-50, 54, 55, 60, and 67). The three TCFs have a number of common features, including their four similar regions, A to D. The N-terminal A domain is the Ets DNA binding domain. The B domain interacts with the serum response factor (SRF) and is required for ternary complex formation. The C-terminal C domain is a transcription activation domain that is turned on by phosphorylation by mitogen-activated protein (MAP) kinases. The D domain is a docking site for MAP kinases. The TCFs bind to Ets binding sites (EBSs

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“…18 -21 Interestingly, FOXO1 was previously shown to bind to the insulin response element (IRE) of the PAI-1 promoter, although it had little effect on insulin-driven PAI-1 expression. 22,23 This suggests that another Fox protein(s) plays a role in insulin-mediated induction of the PAI-1 gene.FOXC2 is shown to be upregulated by insulin signaling in adipocytes and functions as a key regulator in adipose tissues in counteracting insulin resistance in adult mice as well as human subjects of insulin resistance or obesity. 24,25 FOXC2 upregulates the transcription of the RI subunit of protein kinase A (PKA) to augment the ␤-adrenergic-cAMP-PKA response, leading to increased sensitivity to insulin.…”

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Foxc2 Is a Common Mediator of Insulin and Transforming Growth Factor β Signaling to Regulate Plasminogen Activator Inhibitor Type I Gene Expression

Fujita

Kang

Eren

et al. 2006

Circulation Research

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Abstract-Elevated plasma levels of plasminogen activator inhibitor type I (PAI-1), a significant risk factor of ischemic heart disease, are associated with insulin resistance in which insulin and transforming growth factor (TGF)-␤ play a pivotal role in regulating PAI-1 production. Forkhead transcription factor FOXC2 is an important regulator of insulin resistance. However, the underlying molecular mechanisms to link FOXC2 to PAI-1 levels in insulin resistance remain to be elucidated. Here, we demonstrate that Foxc2 is a common transcriptional activator of insulin and TGF-␤ signaling to directly regulate PAI-1 expression via 2 distinct target sites, an insulin response element (IRE) and a novel forkhead-binding element (FBE), adjacent to a Smad-binding site. We found that in adipocytes and endothelial cells Foxc2 mediates insulin action competing with another Forkhead protein, FOXO1, via the insulin response element, and simultaneously cooperate with the TGF-␤/Smad pathway to transactivate PAI-1. Importantly, Foxc2 haploinsufficiency in mice significantly attenuates TGF-␤1-induced PAI-1 expression in the cardiovascular system and adipose tissue. Taken Key Words: plasminogen activator inhibitor-1 promoter Ⅲ insulin response element Ⅲ TGF-␤ Ⅲ response site Ⅲ forkhead transcription factor I nsulin resistance, defined as an attenuated responsiveness to insulin, is widely recognized as a key component of prediabetic state and obesity. Clinical studies have identified a strong link between insulin resistance and ischemic heart disease. 1,2 Nevertheless, little is known about the underlying mechanisms to elucidate their precise interaction.Plasminogen activator inhibitor type 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation, and animal studies have identified PAI-1 as a mediator of ischemic heart disease in obesity. 3 PAI-1 is synthesized in many tissues, including vascular endothelium and adipose tissue. [3][4][5] Elevated plasma levels of PAI-1 are strongly associated with increased risk of ischemic heart disease. 2,6 Plasma levels of PAI-1 are determined by genetic, hormonal, 7,8 circadian, 9,10 and metabolic factors, such as fatty acids 11 and glucose. 12 In the context of insulin resistance, as well as obesity and type 2 diabetes mellitus, several signaling pathways are known to play important roles in regulating PAI-1 gene expression. Insulin per se induces PAI-1 even in insulin-resistant adipocytes and insulin-resistant mice. 13 Transforming growth factor (TGF)-␤ levels are elevated in adipose tissues and TGF-␤ administration increases PAI-1 in genetically obese (ob/ob) mice. 14 Elevated levels of tumor necrosis factor ␣ also increase PAI-1 levels in adipose tissues of obese mice. 15 Importantly, inflammatory process has recently emerged as a critical biological mechanism underlying obesity-related insulin resistance. 16,17 However, the mechanisms underlying transcriptional regulation of PAI-1 in insulin resistance are not well understood.Forkhead box (Fox) proteins constitute a la...

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A Forkhead/Winged Helix-related Transcription Factor Mediates Insulin-increased Plasminogen Activator Inhibitor-1 Gene Transcription

Cited by 22 publications

References 59 publications

Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

The Ternary Complex Factor Net Regulates Cell Migration through Inhibition of PAI-1 Expression

Foxc2 Is a Common Mediator of Insulin and Transforming Growth Factor β Signaling to Regulate Plasminogen Activator Inhibitor Type I Gene Expression

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