scholarly journals Hyperoxia-induced NF-κB activation occurs via a maturationally sensitive atypical pathway

2009 ◽  
Vol 296 (3) ◽  
pp. L296-L306 ◽  
Author(s):  
Clyde J. Wright ◽  
Tiangang Zhuang ◽  
Ping La ◽  
Guang Yang ◽  
Phyllis A. Dennery
Keyword(s):  
Nuclear Translocation ◽  
Fetal Lung ◽  
Dominant Negative ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Normal Lung ◽  
Adult Lung ◽  
Fetal Cells ◽  
Reporter Activity ◽  
Tnf Α

NF-κB activation is exaggerated in neonatal organisms after oxidant and inflammatory insults, but the reason for this and the downstream effects are unclear. We hypothesized that specific phosphorylation patterns of IκBα could account for differences in NF-κB activation in hyperoxia-exposed fetal and adult lung fibroblasts. After exposure to hyperoxia (>95% O2), nuclear NF-κB binding increased in fetal, but not adult, lung fibroblasts. Unique to fetal cells, phosphorylation of IκBα on tyrosine 42, rather than serine 32/36 as seen in TNF-α-exposed cells, preceded NF-κB nuclear translocation. In fetal cells stably transfected with an NF-κB-driven luciferase reporter, hyperoxia significantly suppressed reporter activity, in contrast to increased reporter activity after TNF-α incubation. Targeted gene profiling analysis showed that hyperoxia resulted in decreased expression of multiple genes, including proapoptotic factors. Transfection with a dominant-negative IκBα (Y42F), which cannot be phosphorylated on tyrosine 42, resulted in upregulation of multiple proapoptotic genes. In support of this finding, caspase-3 activity and DNA laddering were specifically increased in fetal lung fibroblasts expressing Y42F after exposure to hyperoxia. These data demonstrate a unique pathway of NF-κB activation in fetal lung fibroblasts after exposure to hyperoxia, whereby these cells are protected against apoptosis. Activation of this pathway in fetal cells may prevent the normal pattern of fibroblast apoptosis necessary for normal lung development, resulting in aberrant lung morphology in vivo.

scholarly journals Activation of Nuclear Factor κb and bcl-x Survival Gene Expression by Nerve Growth Factor Requires Tyrosine Phosphorylation of IκBα

2001 ◽  
Vol 152 (4) ◽  
pp. 753-764 ◽  
Author(s):  
Nguyen Truc Bui ◽  
Antonia Livolsi ◽  
Jean-Francois Peyron ◽  
Jochen H.M. Prehn
Keyword(s):  
Gene Expression ◽  
Tyrosine Phosphorylation ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Nuclear Factor ◽  
Human Neuroblastoma ◽  
Tnf Α

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-κB (NFκB). We investigated the effect of NGF on the expression of Bcl-xL, an anti–apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1–10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFκB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFκB p65 subunit. NGF-induced NFκB activity and Bcl-xL expression were inhibited in cells overexpressing the NFκB inhibitor, IκBα. Unlike tumor necrosis factor-α (TNF-α), however, NGF-induced NFκB activation occurred without significant degradation of IκBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein–tagged IκBα. Moreover, in contrast to TNF-α, NGF failed to phosphorylate IκBα at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IκBα potently suppressed NFG-, but not TNF-α–induced NFκB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-α–, but not NGF-induced NFκB activation. We conclude that NGF and TNF-α induce different signaling pathways in neurons to activate NFκB and bcl-x gene expression.

scholarly journals Antagonizing Effects of Clematis apiifolia DC. Extract against Benzo[a]pyrene-Induced Damage to Human Keratinocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Seung Eun Lee ◽  
See-Hyoung Park ◽  
Ju Ah Yoo ◽  
Kitae Kwon ◽  
Ji Woong Kim ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Human Keratinocytes ◽  
Antioxidant Response ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Cytochrome P450 1A1 ◽  
Independent Manner ◽  
Reporter Activity ◽  
Aryl Hydrocarbon

Background. Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon present in the atmosphere, has cytotoxic and carcinogenic effects. There have been no reports to demonstrate involvement of Clematis apiifolia DC. extract (CAE) in B[a]P-induced effects. This study was conducted to investigate the effect of CAE on B[a]P-induced effects and to elucidate its mechanism of action in HaCaT human keratinocytes. CAE inhibited aryl hydrocarbon receptor (AhR) signaling by decreasing both XRE reporter activity and expression of cytochrome P450 1A1 (CYP1A1) induced by B[a]P treatment in HaCaT cells. We also found that B[a]P-induced nuclear translocation of AhR and production of reactive oxygen species (ROS) and proinflammatory cytokines were attenuated by CAE treatment. CAE treatment suppressed B[a]P-induced phosphorylation of Src (Tyr416). In addition, dasatinib, a Src inhibitor, also inhibited B[a]P-induced nuclear translocation of AhR, similar to CAE treatment. In addition, CAE activated antioxidant response element (ARE) signaling by increasing ARE luciferase reporter activity and expression of ARE-dependent genes such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), NAD(P)H dehydrogenase [quinone] 1 (NQO1), and heme oxygenase-1 (HO-1). Nuclear translocation of Nrf2 by CAE was demonstrated by Western blot analysis and immunocytochemistry. The effects of CAE on ARE signaling were attenuated by knockdown of the Nrf2 gene. Inhibition of AhR signaling and activation of antioxidant activity by CAE operated in a reciprocally independent manner as evidenced by AhR and Nrf2 siRNA experiments. These findings indicate that CAE exerts protective effects against B[a]P by inhibiting AhR signaling and activating Nrf2-mediated signaling, suggesting its potential in protection from harmful B[a]P-containing pollutants.

The oncogeneTrop2regulates fetal lung cell proliferation

2011 ◽  
Vol 301 (4) ◽  
pp. L478-L489 ◽  
Author(s):  
Annie R. A. McDougall ◽  
Stuart B. Hooper ◽  
Valerie A. Zahra ◽  
Foula Sozo ◽  
Camden Y. Lo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fetal Lung ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Lung Growth ◽  
Ki 67 ◽  
Alveolar Epithelial ◽  
Fetal Rat ◽  
Lung Expansion

The factors regulating growth of the developing lung are poorly understood, although the degree of fetal lung expansion is critical. The oncogene Trop2 (trophoblast antigen 2) is upregulated during accelerated fetal lung growth, and we hypothesized that it may regulate normal fetal lung growth. We investigated Trop2 expression in the fetal and neonatal sheep lung during accelerated and delayed lung growth induced by alterations in fetal lung expansion, as well as in response to glucocorticoids. Trop2 expression was measured using real-time PCR and localized spatially using in situ hybridization and immunofluorescence. During normal lung development, Trop2 expression was higher at 90 days gestational age (GA; 4.0 ± 0.8) than at 128 days GA (1.0 ± 0.1), decreased to 0.5 ± 0.1 at 142 days GA (full term ∼147 days GA), and was positively correlated to lung cell proliferation rates ( r = 0.953, P < 0.005). Trop2 expression was regulated by fetal lung expansion, but not by glucocorticoids. It was increased nearly threefold by 36 h of increased fetal lung expansion ( P < 0.05) and was reduced to ∼55% of control levels by reduced fetal lung expansion ( P < 0.05). Trop2 expression was associated with lung cell proliferation during normal and altered lung growth, and the TROP2 protein colocalized with Ki-67-positive cells in the fetal lung. TROP2 was predominantly localized to fibroblasts and type II alveolar epithelial cells. Trop2 small interfering RNA decreased Trop2 expression by ∼75% in cultured fetal rat lung fibroblasts and decreased their proliferation by ∼50%. Cell viability was not affected. This study demonstrates that TROP2 regulates lung cell proliferation during development.

scholarly journals Toll-Like Receptor 9-Dependent Macrophage Activation by Entamoeba histolytica DNA

2007 ◽  
Vol 76 (1) ◽  
pp. 289-297 ◽  
Author(s):  
Catherine P. A. Ivory ◽  
Michael Prystajecky ◽  
Christian Jobin ◽  
Kris Chadee
Keyword(s):  
Entamoeba Histolytica ◽  
Defense Mechanism ◽  
Nuclear Translocation ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Toll Like Receptor ◽  
Intestinal Protozoan ◽  
Recognition Mechanism ◽  
Innate Defense ◽  
Tnf Α

ABSTRACT Activation of the innate immune system by bacterial DNA and DNA of other invertebrates represents a pathogen recognition mechanism. In this study we investigated macrophage responses to DNA from the intestinal protozoan parasite Entamoeba histolytica. E. histolytica genomic DNA was purified from log-phase trophozoites and tested with the mouse macrophage cell line RAW 264.7. RAW cells treated with E. histolytica DNA demonstrated an increase in levels of tumor necrosis factor alpha (TNF-α) mRNA and protein production. TNF-α production was blocked by pretreatment with chloroquine or monensin. In fact, an NF-κB luciferase reporter assay in HEK cells transfected with human TLR9 demonstrated that E. histolytica DNA signaled through Toll-like receptor 9 (TLR9) in a manner similar to that seen with CpG-ODN. Immunofluorescence assays confirmed NF-κB activation in RAW cells, as seen by nuclear translocation of the p65 subunit. Western blot analysis demonstrated mitogen-activated protein kinase activation by E. histolytica DNA. E. histolytica DNA effects were abolished in MYD88−/− mouse-derived macrophages. In the context of disease, immunization with E. histolytica DNA protected gerbils from an E. histolytica challenge infection. Taken together, these results demonstrate that E. histolytica DNA is recognized by TLR9 to activate macrophages and may provide an innate defense mechanism characterized by the induction of the inflammatory mediator TNF-α.

scholarly journals Protective Effects of Maclurin against Benzo[a]pyrene via Aryl Hydrocarbon Receptor and Nuclear Factor Erythroid 2-Related Factor 2 Targeting

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1189
Author(s):  
Jangsoon Kim ◽  
See-Hyoung Park ◽  
Seyoung Yang ◽  
Sae Woong Oh ◽  
Kitae Kwon ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Translocation ◽  
Radical Scavenging ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Response Element ◽  
Reporter Activity ◽  
Aryl Hydrocarbon

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon formed during the incomplete combustion of organic matter, has harmful effects. Therefore, much research is ongoing to develop agents that can mitigate the effects of B[a]P. The aim of this study was to examine the effect of maclurin, one component of the branches of Morus alba L., on the B[a]P-induced effects in HaCaT cells, a human keratinocyte cell line. Maclurin treatment inhibited aryl hydrocarbon receptor (AHR) signaling as evidenced by reduced xenobiotic response element (XRE) reporter activity, decreased expression of cytochrome P450 1A1 (CYP1A1), and reduced nuclear translocation of AHR. The B[a]P-induced dissociation of AHR from AHR-interacting protein (AIP) was suppressed by maclurin. Maclurin also inhibited the production of intracellular reactive oxygen species (ROS) induced by B[a]P. In addition, the antioxidant property of maclurin itself was demonstrated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Furthermore, maclurin activated antioxidant response element (ARE) signaling through enhancement of ARE luciferase reporter activity and the expression of ARE-dependent genes including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). Nrf2 activation and its nuclear translocation were promoted by maclurin through p38 MAPK activation. These data indicate that maclurin had antagonistic activity against B[a]P effects through activation of Nrf2-mediated signaling and inhibition of AHR signaling and, suggesting its potential in protecting from harmful B[a]P-containing pollutants.

scholarly journals Glucocorticoid signalling drives reduced versican levels in the fetal mouse lung

2020 ◽  
Vol 64 (3) ◽  
pp. 155-164
Author(s):  
Kelly L Short ◽  
A Daniel Bird ◽  
Bennet K L Seow ◽  
Judy Ng ◽  
Annie R A McDougall ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fetal Lung ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Mouse Lung ◽  
Mrna Levels ◽  
Lung Maturation ◽  
Fetal Mouse ◽  
Distal Lung

Glucocorticoid (GC) signaling via the glucocorticoid receptor (GR) is essential for lung maturation in mammals. Previous studies using global or conditional mouse model knockouts of the GR gene have established that GR-mediated signaling in the interstitial mesenchyme of the fetal lung is critical for normal lung development. Screens for downstream GC-targets in conditional mesenchymal GR deficient mouse lung (GRmesKO) identified Versican (Vcan), an important extracellular matrix component and cell proliferation regulator, as a potential GR-regulated target. We show that, of the five major VCAN isoforms, the VCAN-V1 isoform containing the GAGβ domain is the predominant VCAN isoform in the fetal mouse lung distal mesenchyme at both E16.5 and E18.5, whereas the GAGα-specific VCAN-V2 isoform was only localized to the smooth muscle surrounding proximal airways. Both Vcan-V1 mRNA and protein levels were strongly overexpressed in the GRmesKO lung at E18.5. Finally, we investigated the GC regulation of the ECM protease ADAMTS 12 and showed that Adamts 12 mRNA levels were markedly reduced at E18.5 in GRmesKO fetal mouse lung and were strongly induced by both cortisol and betamethasone in cultures of primary rat fetal lung fibroblasts. ADAMTS12 protein immunoreactivity was also strongly increased in the distal lung at E18.5, after dexamethasone treatment in utero. In summary, glucocorticoid signaling via GR represses GAGβ domain-containing VCAN isoforms in distal lung mesenchyme in vivo by repressing Vcan gene expression and, in part, by inducing the ECM protease ADAMTS12, thereby contributing to the control of ECM remodelling and lung cell proliferation prior to birth.

Transfection of human endothelial cells with HIV-1tatgene activates NF-κB and enhances monocyte adhesion

2002 ◽  
Vol 283 (6) ◽  
pp. H2315-H2321 ◽  
Author(s):  
Galen M. Pieper ◽  
Cara L. Olds ◽  
Jeffrey D. Bub ◽  
Paul F. Lindholm
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Dominant Negative Mutant ◽  
Human Leukemia ◽  
Monocyte Adhesion ◽  
Human Endothelial Cells ◽  
Reporter Activity ◽  
Hiv 1

Human immunodeficiency virus (HIV)-1 Tat released from HIV-1-infected monocytes is believed to enter other cells via an integrin-facilitated pathway, resulting in altered gene expression. Indeed, exogenous Tat protein can increase cell adhesion molecule gene expression in human endothelial cells. Signaling pathways initiated by Tat in endothelial cells are not known. We evaluated the ability of endogenous tat to stimulate monocyte adhesion via activation of nuclear factor-κB (NF-κB) within human umbilical vein endothelial cells. Transfection with pcTat, but not control vector DNA, increased NF-κB binding activity, NF-κB luciferase reporter activity, and monocyte adhesion. pcTat also increased κB-dependent HIV-1-LTR-CAT reporter activity 28-fold compared with a 3-fold increase produced by transfection with an equivalent amount of pcTax (from human leukemia virus). The pcTat-induced increase in pNF-κB-Luc activity and monocyte adhesion to endothelial cells was blocked by cotransfection with dominant-negative mutant IκBα and by incubation with 10 mM aspirin. We conclude that monocyte adhesion to human endothelial cells stimulated by pcTat is mediated via an NF-κB-dependent mechanism. Furthermore, inhibition studies using aspirin suggest that pcTat-stimulated NF-κB activation and monocyte adhesion occur via a redox-sensitive mechanism.

scholarly journals Chrysophanol administration alleviates bleomycin-induced pulmonary fibrosis by inhibiting lung fibroblast proliferation and Wnt/β-catenin signaling

2020 ◽  
Vol 19 (5) ◽  
pp. 971-976
Author(s):  
Xiangwei Qi ◽  
Yamei Ou ◽  
Ying Xie ◽  
Kangrong Cai ◽  
Hualin Gan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Nuclear Translocation ◽  
Interstitial Fibrosis ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Collagen Deposition ◽  
Fibroblast Proliferation ◽  
Tnf Α ◽  
Ifn Γ ◽  
E Cadherin

Purpose: To determine the functional effect of chrysophanol (CH) on bleomycin (BLM)-induced pulmonary fibrosis (PF) and reveal its mechanism of action.Methods: A mouse model of PF was established by intratracheal instillation of BLM (5 mg/kg), prior to CH administration. Masson’s trichrome staining was used to analyze interstitial fibrosis and collagen deposition. Hydroxyproline (HYP) content was measured, and lung fibroblast viability determined by MTT assay. Bronchoalveolar lavage fluid (BALF) was collected, and levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and interferon-γ (IFN-γ) were evaluated using enzyme-linked immunosorbent assays (ELISA). Expression of cell signaling, adhesion, and apoptotic proteins were determined by western blotting.Results: Administration of CH reduced collagen deposition and HYP content, downregulated α-smooth muscle actin, upregulated E-cadherin, and decreased the levels of TNF-α, IL-1β, IL-6, and IFN-γ in BLM-treated mice. The viability of lung fibroblasts was also reduced, and Bcl-2-associated X protein and cleaved caspase-3 were upregulated after CH treatment in BLM-treated mice. In addition, CH treatment in BLM-treated mice significantly increased levels of cytoplasmic β-catenin but decreased its expression in the nucleus.Conclusion: Administration of CH alleviated BLM-induced PF by inhibiting lung fibroblast proliferation and nuclear translocation of β-catenin. Thus, this study provides a potential therapeutic strategy for PF. Keywords: Chrysophanol, Bleomycin, Pulmonary fibrosis, Hydroxyproline, E-cadherin

scholarly journals Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Human Fetal Lung and Regulation of Its Expression by Interleukin-1β and Cortisol

2009 ◽  
Vol 94 (1) ◽  
pp. 306-313 ◽  
Author(s):  
Zhen Yang ◽  
Ping Zhu ◽  
Chunming Guo ◽  
Xiaoou Zhu ◽  
Kang Sun
Keyword(s):  
Mrna Expression ◽  
Fetal Lung ◽  
Hydroxysteroid Dehydrogenase ◽  
Cyclooxygenase 2 ◽  
Dominant Negative ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Proinflammatory Mediators ◽  
Human Fetal Lung

Abstract Context: Glucocorticoids are crucial in fetal lung function. The amount of cortisol available to its receptors is increased by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Glucocorticoids and IL-1β are known to induce 11β-HSD1 expression in a number of tissues, but controversial results were obtained with regard to 11β-HSD1 expression in human fetal lung. Objective: We examined the expression of 11β-HSD1 and its regulation by cortisol and IL-1β in human fetal lung. Results: Immunohistochemistry revealed 11β-HSD1 expression in the epithelium and mesenchymal layer of the small bronchus and bronchiole of human fetal lung at 8 months but not at 4 months gestation, which was confirmed by PCR revealing 11β-HSD1 mRNA expression in the fetal lung tissue. By using a cell line derived from human fetal lung fibroblasts, we demonstrated that cortisol (10−5 to 10−3 mmol/liter) or IL-1β (0.1 to 10 ng/ml) induced 11β-HSD1 mRNA expression in a concentration-dependent manner. The induction of 11β-HSD1 by IL-1β was further increased by cortisol, whereas the induction of cyclooxygenase 2 by IL-1β was inhibited by cortisol. Nuclear factor κB activation inhibitor could only block the induction of cyclooxygenase 2 but not 11β-HSD1 by IL-1β, suggesting that different mechanisms were utilized by IL-1β in the regulation of 11β-HSD1 versus proinflammatory mediators. Global inhibition of CCAAT-enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression plasmid could attenuate the induction of 11β-HSD1 by IL-1β, suggesting that C/EBPs may mediate the induction of 11β-HSD1 by IL-1β. Conclusions: 11β-HSD1 is expressed in human fetal lung; cortisol and IL-1β could synergistically induce its expression.

Abstract 725: Protein Kinase C delta Inhibits Type I Collagen Basal Expression through CCAAT-binding Factor and c-Krox in Vascular Smooth Muscle Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kentaro Kamiya ◽  
Andrew Zohlman ◽  
Amy Rapp ◽  
Chunjie Wang ◽  
K. Craig Kent ◽  
...  
Keyword(s):  
Type I Collagen ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Dominant Negative Mutant ◽  
Type I ◽  
Reporter Activity ◽  
Collagen Expression ◽  
Basal Expression ◽  
Kinase C ◽  
Binding Factor

Protein Kinase C delta (PKCδ) regulates multiple functions in vascular smooth muscle cells (VSMCs) including proliferation, migration, and apoptosis. In previous studies, we have demonstrated that PKCδ activity is necessary for TGFβ-induced fibronectin production in VSMCs. The purpose of the current study is to understand the role of this kinase in regulation of type I collagen synthesis. Using A10 VSMCs derived from rat thoracic aorta, we showed that TGFβ (5ng/ml x 48 hours) increased type I collagen expression. Pretreatment of A10 with Rottlerin (2uM, 1 hour), a selective inhibitor of PKCδ, dramatically increased type I collagen basal expression independent of TGFβ. To understand the mechanism involved with PKCδ, we used a Luciferase reporter that contains the human COL1A2 promoter (−772 to +58). Rottlerin stimulated the Luciferase reporter activity by 3.53±0.13 fold (n=3, p<0.01). Moreover, inhibition of PKCδ with a dominant negative mutant led to upregulation of reporter activity (1.77±0.15 fold induction, n=3, p<0.01), while activation of PKCδ with a constitutive active mutant reduced collagen reporters (0.19±0.02 fold reduction, n=3, p<0.01). Using a series of 5′ deletions of COL1A2/Luciferase constructs (−772, −353, and −108), we narrowed the location of the PKCδ-response element to the -108/+58 region of the COL1A2 promoter, which is distinct from the TGFβ response element that is further upstream. This region contains a CCAAT motif and a c-Krox motif that have been previously implicated in collagen expression. Using a gel shift assay, we found that inhibition of PKCδ with Rottlerin or the dominant negative mutant increased the binding of CCAAT-binding Factor (CBF) to the CCAAT motif but decreased the binding at the c-Krox site. Taken together, our data indicate that PKCδ inhibits type I collagen basal expression by affecting its gene transcription through a mechanism involving CBF and c-Krox in VSMCs. We believe that PKCδ is one of the key players in mediating extracellular matrix production and could contribute to pathogenesis of vascular diseases.

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