A pervasive role of histone acetyltransferases and deacetylases in an NF-κB-signaling code

Calao, Miriam; Burny, Arsène; Quivy, Vincent; Dekoninck, Ann; Lint, Carine Van

doi:10.1016/j.tibs.2008.04.015

Cited by 118 publications

(109 citation statements)

References 84 publications

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“…Recent studies have shown that histone deacetylase inhibitors could prevent excessive inflammatory response by regulating the activation of the transcription factor NF-jB in models of systemic immune activation in vitro and in vivo (Blanchard & Chipoy, 2005;Dokmanovic & Marks, 2005;Glozak et al, 2005;Aung et al, 2006;Calao et al, 2008). To study epigenetic regulatory mechanism of miR-146a associated with NF-jB activity during aging, we further confirmed the expression features of miR-146 in LPS-treated macrophag- es from young and aged mice in vitro.…”

Section: Discussionmentioning

confidence: 53%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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SummaryAge-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1b and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-jB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-jB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.

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Section: Discussionmentioning

confidence: 53%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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“…67 Exactly how the AMPK modifies NF-B activity is not entirely clear as the effects on DNA binding are relatively weak, and a strong nuclear translocation of the active NF-B complex has yet to be described. It is tempting to speculate, however, that the acetylation of the NF-B by p300 68 is involved in this response.…”

Section: Pgc-1␣mentioning

confidence: 99%

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

Fißlthaler

Fleming

2009

Circulation Research

276

283

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Abstract-The AMP-activated protein kinase (AMPK) was initially identified as the kinase that phosphorylates the 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. As the name suggests, the AMPK is activated by increased intracellular concentrations of AMP, and is generally described as a "metabolite-sensing kinase" and when activated initiates steps to conserve cellular energy. Although there is a strong link between the activity of the AMPK and metabolic control in muscle cells, the activity of the AMPK in endothelial cells can be regulated by stimuli that affect cellular ATP levels, such as hypoxia as well as by fluid shear stress, Ca 2ϩ -elevating agonists, and hormones such as adiponectin. To date the AMPK in endothelial cells has been implicated in the regulation of fatty acid oxidation, small G protein activity and nitric oxide production as well as inflammation and angiogenesis. Moreover, there is evidence indicating that the activation of the AMPK may help to prevent the vascular complications associated with the metabolic syndrome. Key Words: angiogenesis Ⅲ nitric oxide synthase Ⅲ atherosclerosis Ⅲ 3-hydroxy-3-methylglutaryl coenzyme A Ⅲ energy metabolism T he AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine protein kinase consisting of the catalytic subunit (␣) and 2 regulatory subunits (␤ and ␥) that exist as multiple isoforms and splice variants, resulting in the generation of 12 possible heterotrimeric combinations. As its name suggests, the AMPK is activated in many different cell types by increased intracellular concentrations of AMP and is generally referred to as a "metabolite-sensing kinase." Indeed, the AMPK is activated following heat shock, vigorous exercise, hypoxia/ischemia, and starvation and appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, skeletal muscle fatty acid oxidation, and protein synthesis (reviewed recently 1,2 ). Although the complex picture regarding the regulation of AMPK activity is far from complete, it seems safe to state that the AMPK determines whole body insulin sensitivity and may prevent insulin resistance, in part, by inhibiting pathways that antagonize insulin signaling. Through its effects on signaling, metabolism, and gene expression, the AMPK enhances insulin sensitivity and may reduce the risk of type 2 diabetes. 3 The 2 previous review articles in this series have focused on the role of the AMPK in metabolic control and insulin signaling 4 and in the heart. 5 This review focuses on the role of the AMPK in vascular cells and the data implicating defects in AMPK signaling in the development of vascular disease. Activation of the AMPKEach subunit within the heterotrimeric AMPK complex has a distinct structure and function and their interaction is necessary for the modulation of kinase activity. The ␣ subunits Ori...

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“…The relevant mechanisms of action are likely to be diverse, as several nonhistone proteins have emerged as targets for proinflammatory HDAC activity, including MAPK phosphatase-1 79 and the transcription factors STAT1, [80][81][82][83]84,85 and nuclear factor B. 86 HDACis suppress proinflammatory cytokine release in cultured PBMCs, macrophages, T cells and epithelial cells [87][88][89][90][91][92][93][94][95] and suppress inflammation in animal models of concanavalin-A-induced hepatitis 92 and lipopolysaccharideinduced endotoxemia. 89,91 HDACis have received significant attention as novel agents for rheumatoid arthritis, 96 capable of reducing inflammation, synovial fibroblast proliferation, joint swelling and bone and cartilage destruction in rodent models of rheumatoid arthritis.…”

Section: Antiinflammatory Effects Of Hdacismentioning

confidence: 99%

Protein Acetylation in the Cardiorenal Axis

Bush

McKinsey

2010

Circulation Research

114

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Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-tomesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs. (Circ Res. 2010; 106:272-284.)Key Words: acetylation Ⅲ histone deacetylase Ⅲ heart failure Ⅲ kidney failure Ⅲ fibrosis I t has been estimated that more than 5 million adults in the United States experience heart failure, and more than 20 million adults show signs of chronic kidney disease (CKD). 1,2 Of the patients with heart failure, Ϸ50% experience heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure, which is characterized at the cellular level by myocyte hypertrophy and activation of extracellular matrix (ECM)-producing fibroblasts. Current standard of care for systolic heart failure (eg, ACE inhibitors and ␤-blockers) provide little to no benefit to patients with HFpEF. 3 Likewise, therapy for CKD primarily focuses on lowering blood pressure through modulation of the renin-angiotensin system and maintaining blood glucose control, and this strategy only minimally slows the glomerular injury and insidious fibrotic mechanisms that culminate in end-stage renal disease. 4 The high rate of morbidity and mortality in patients with HFpEF and CKD underscores the urgent need for novel therapeutics. Histone deacetylases (HDACs) are emerging as key players in the pathogenesis of these diseases, suggesting unexpected potential for pharmacological inhibitors of HDACs in the treatment of disorders of the cardiorenal axis.Histone acetyltransferases (HATs) and HDACs act in an opposing manner to control the acetylation state of proteins. The most well characterized role for protein acetylation is in Original received September 15, 2009; revision received October 6, 2009; accepted October 27, 2009 the control of gene transcription. Acetylation of the -amino groups of lysine residues in nucleosomal histone tails by HATs is thought to relax chromatin structure by weakening the interaction of the positively charged histone tails with the negatively charged phosphate backbone of DNA, allowing access of transcriptional activators and gene induction. Deacetylation of histones by HDACs alters the electrostatic properties of chromatin in a manner that favors gene repression. Interestingly, a recent genome-wide chromatin immunoprecipitation analysis revealed preferen...

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A pervasive role of histone acetyltransferases and deacetylases in an NF-κB-signaling code

Cited by 118 publications

References 84 publications

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

Protein Acetylation in the Cardiorenal Axis

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