Smad6s Regulates Plasminogen Activator Inhibitor-1 through a Protein Kinase C-β-dependent Up-regulation of Transforming Growth Factor-β

Berg, David T.; Myers, Laura J.; Richardson, Mark A.; Sandusky, George E.; Grinnell, Brian W.

doi:10.1074/jbc.c400579200

Cited by 19 publications

(16 citation statements)

References 58 publications

(44 reference statements)

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“…4A, treatment of cells with TGF-␤ resulted in a significant increase in binding to the TCF11/MafG site, which could be competed with the cold binding site. Previous studies have shown that Smad6-short and Smad7 can agonize and antagonize TGF-␤ signaling in vascular cells, respectively (16). Overexpression of Smad6-short, which enhances TGF-␤ signaling, resulted in an increase in TCF11/MafG binding (Fig.…”

Section: Tgf-␤1 Induces Tcf11/mafg Binding To the Inos Promoter In A mentioning

confidence: 99%

“…In some experiments, a control pCIneo vector (Promega, Madison, WI) or the expression vectors for Smad6-short and Smad7 (16) were transfected into cells with Lipofectin, and the level of TCF11/MafG binding was determined in cell lysates 24 h later. The effect of TGF-␤ (1 ng/ml) on TCF11/MafG levels was determined 24 h after addition to the maintenance medium.…”

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confidence: 99%

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Negative Regulation of Inducible Nitric-oxide Synthase Expression Mediated through Transforming Growth Factor-β-dependent Modulation of Transcription Factor TCF11

Berg

Gupta

Richardson

et al. 2007

Journal of Biological Chemistry

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Inducible nitric-oxide synthase (iNOS) plays a central role in the regulation of vascular function and response to injury. A central mediator controlling iNOS expression is transforming growth factor-␤ (TGF-␤), which represses its expression through a mechanism that is poorly understood. We have identified a binding site in the iNOS promoter that interacts with the nuclear heterodimer TCF11/MafG using chromatin immunoprecipitation and mutation analyses. We demonstrate that binding at this site acts to repress the induction of iNOS gene expression by cytokines. We show that this repressor is induced by TGF-␤1 and by Smad6-short, which enhances TGF-␤ signaling. In contrast, the up-regulation of TCF11/MafG binding could be suppressed by overexpression of the TGF-␤ inhibitor Smad7, and a small interfering RNA to TCF11 blocked the suppression of iNOS by TGF-␤. The binding of TCF11/MafG to the iNOS promoter could be enhanced by phorbol 12-myristate 13-acetate and suppressed by the protein kinase C inhibitor staurosporine. Moreover, the induction of TCF11/MafG binding by TGF-␤ and Smad6-short could be blocked by staurosporine, and the effect of TGF-␤ was blocked by the selective protein kinase C inhibitor calphostin C. Consistent with the in vitro data, we found suppression of TCF11 coincident with iNOS upregulation in a rat model of endotoxemia, and we observed a highly significant negative correlation between TCF11 and nitric oxide production. Furthermore, treatment with activated protein C, a serine protease effective in septic shock, blocked the down-regulation of TCF11 and suppressed endotoxin-induced iNOS. Overall, our results demonstrate a novel mechanism by which iNOS expression is regulated in the context of inflammatory activation.Nitric oxide (NO) is an important regulator and mediator of numerous and diverse processes, including vascular function, neurotransmission, tumor biology, and innate immune response (reviewed in Ref. 1). The production and balance of NO from inducible nitric-oxide synthase (iNOS) 3 play an important role in septic shock because overexpression mediates vascular collapse and cardiac dysfunction (2) and contributes to multiple organ dysfunction (reviewed in Ref.3). Selective iNOS inhibition has been shown to attenuate the hemodynamic alterations in sepsis models (4). During acute inflammatory insult, iNOS is synergistically induced by the TH-1 cytokines tumor necrosis factor-␣, interleukin-1␤, and interferon-␥ (5). Following cytokine activation and iNOS induction, vascular smooth muscle cells produces high levels of NO (6). A key factor in controlling iNOS expression is transforming growth factor-␤ (TGF-␤), which has been shown to suppress the expression of iNOS at the mRNA level in a variety of cells (6 -8), and anti-TGF antibody has been shown to block the suppression of iNOS in the vasculature (9). Moreover, in an endotoxin model of septic shock, TGF-␤1 treatment markedly reduced iNOS mRNA in several organs and blocked the lipopolysaccharide (LPS)-induced hypotension (10).Although t...

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Section: Tgf-␤1 Induces Tcf11/mafg Binding To the Inos Promoter In A mentioning

confidence: 99%

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confidence: 99%

Negative Regulation of Inducible Nitric-oxide Synthase Expression Mediated through Transforming Growth Factor-β-dependent Modulation of Transcription Factor TCF11

Berg

Gupta

Richardson

et al. 2007

Journal of Biological Chemistry

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“…This site is adjacent to 1 of the TRSs ( Figure 2A) and has recently been shown to be a putative FoxD1-binding site. 40 Because FoxC1, FoxC2, and FoxO1 are coexpressed in endothelial and preadipocytic cell lines (supplemental Figure II), we examined whether these Fox proteins directly bind to the Fox-binding sites on the PAI-1 promoter ( Figure 2B). Specific complexes were formed between IRE or FBE probe and recombinant Fox proteins.…”

Section: Foxc2 Regulates the Pai-1 Promoter Via Two Fox-binding Sitesmentioning

confidence: 99%

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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“…In contrast, BMP-2 enhances apoptosis by using the PKC-dependent signaling pathway in human osteoblasts (24). It was also reported that Smad6 regulates TGF-h and plasminogen activator inhibitor-1 through a PKC-hdependent mechanism (25), and Smad3 and PKCy mediate TGFh1-induced collagen I expression in human mesangial cells (26). These studies suggest a new mechanism for the regulation of PKC by 1a,25(OH) 2 D 3 and vitamin D 3 analogues that may affect the TGF-h/BMP signaling pathway.…”

Section: Introductionmentioning

confidence: 86%

“…Interestingly, several studies have reported that PKC interacts with the TGF-h/BMP signaling pathway (23)(24)(25). PKC-dependent phosphorylation of the MH1 domain of TGF-h-specific Smads (Smad2/3) led to down-regulation of the growth-inhibitory and apoptotic action of TGF-h (23).…”

Section: Introductionmentioning

confidence: 99%

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Lee

Paul

et al. 2007

Cancer Research

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Bone morphogenetic proteins (BMP) are members of the transforming growth factor-B superfamily, and they play an important role for embryonic development, for bone and cartilage formation, and during carcinogenesis. We have previously shown that the novel Gemini vitamin D 3 analogue, 1A,, inhibited cell proliferation and activated the BMP/Smad signaling pathway in MCF10AT1 breast epithelial cells. In this report, we investigated the upstream signaling pathways responsible for the activation of BMP/Smad signaling by Ro3582. Among seven different serine/threonine kinase inhibitors that we tested, protein kinase C (PKC) inhibitors blocked the effects of Ro3582 on the phosphorylation of Smad1/5, mRNA synthesis for BMP-2 and BMP-6, and cell growth in MCF10AT1 cells. Overexpression of PKCA, but not PKCE, PKCD or PKCZ isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKCA mediates the activation of Smad signaling and inhibition of cell proliferation. Interestingly, the activation of Smad signaling by Ro3582 was shown in Ha-ras-transfected MCF10AT1 cells, but not in the parent cell line (MCF10A without Ras). Inhibiting Ras activity blocked the translocation of PKCA to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582, indicating that Ras is necessary for the activation of PKCA and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKCA pathway in breast epithelial cells. [Cancer Res 2007;67(24):11840-7]

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Smad6s Regulates Plasminogen Activator Inhibitor-1 through a Protein Kinase C-β-dependent Up-regulation of Transforming Growth Factor-β

Cited by 19 publications

References 58 publications

Negative Regulation of Inducible Nitric-oxide Synthase Expression Mediated through Transforming Growth Factor-β-dependent Modulation of Transcription Factor TCF11

Negative Regulation of Inducible Nitric-oxide Synthase Expression Mediated through Transforming Growth Factor-β-dependent Modulation of Transcription Factor TCF11

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

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

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