Rev‐erbα upregulates NF‐κB‐responsive genes in vascular smooth muscle cells

Migita, Hideyuki; Morser, John; Kawai, Kohichi

doi:10.1016/s0014-5793(04)00118-8

Cited by 60 publications

(53 citation statements)

References 39 publications

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“…overexpression contributes to induction of certain pro-inflammatory genes such as IL6 and COX-2 through NF-B pathway by increasing p65 nuclear translocation (8). Similar findings have also been mentioned in astrocytes, where Rev-erb␣ competes with ROR␣ for the up-regulation of IL6 in NF-B-dependent pathway (35).…”

Section: Discussionsupporting

confidence: 68%

“…It is encoded on the opposite strand of the thyroid receptor ␣ (c-erbA␣) gene (6). Rev-erb␣ modulates proinflammatory cytokines through 8) and in that regard is similar to heme, its physiological ligand (5). Rev-erb␣ is structurally unusual in that it lacks the C-terminal tail (helix 12) of the ligand binding domain, which is required for co-activator recognition, hence functions as a transcriptional repressor (9).…”

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confidence: 99%

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Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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Background: Transcriptional modulation of IL10, a cytokine that blocks phagolysosome maturation, is not well understood. Results: This study demonstrates human IL10 gene repression by direct binding of Rev-erb␣ on Rev-DR2 in the proximal promoter. Conclusion: Rev-erb␣ binds to IL10 proximal promoter, represses expression, and impedes Mycobacterium tuberculosis in human macrophages. Significance: This study provides rationale to target Rev-erb␣ as a therapeutic intervention that might support host defense in tuberculosis.Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erb␣ is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erb␣ in monocytes and macrophages. The nuclear localization of Rev-erb␣ in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erb␣ elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erb␣ overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erb␣ binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erb␣ bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.Macrophages are immune system sentinels with a major role to play in both innate and adaptive immunity. They are the key effectors in antimicrobial defense, atherogenesis, autoimmunity, and many other inflammatory diseases (1). Although the activation, function, classification, and plasticity of these cells have been studied extensively with regard to cellular signaling, the cytokine environment, and surface, cellular, or secretory markers, studies of the underlying molecular mechanism have mostly addressed NF-B (2). Similarly, modulation of macrophage function and alteration of disease pathology by small molecules such as heme, lipids, or drugs such as rifampicin are well understood at the translational level of the effectors (3, 4), but the transcriptional mechanism involving interactions of these ligands with transcriptional molecules and the resulting expression patterns have not been investigated.This study focuses on Rev-erb␣, an adopted orphan nuclear receptor that belongs to the steroid/thyroid hormone receptor superfamily and is a known ...

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Section: Discussionsupporting

confidence: 68%

mentioning

confidence: 99%

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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“…The molecular basis of this modulation involves the direct induction of IB␣ transcription, thereby inhibiting the NFB signaling cascade. Conversely, Rev-erb␣ induces the NFB-mediated activation of the inflammatory cascade, for example, Cox-2 (44). Our studies show that attenuation of Rev-erb␤-mediated gene regulation leads to elevated ROR␣ and IB␣ expression in skeletal muscle cells.…”

Section: Figmentioning

confidence: 58%

“…Recent studies (22,44,45) have demonstrated a role of ROR␣ in the inflammation process. For example, ROR␣ has an anti- inflammatory role by inhibiting tumor necrosis factor-␣-induced gene expression (22).…”

Section: Figmentioning

confidence: 99%

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Ramakrishnan

Lau

Burke

et al. 2005

Journal of Biological Chemistry

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Rev-erb␤ is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-␣ (ROR␣). ROR␣ has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Reverb␤ and ROR␣ are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erb␤ has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erb␤ regulates lipid metabolism in skeletal muscle. This lean tissue accounts for >30% of total body weight and 50% of energy expenditure. Moreover, this metabolically demanding tissue is a primary site of glucose disposal, fatty acid oxidation, and cholesterol efflux. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. We utilize ectopic expression in skeletal muscle cells to understand the regulatory role of Rev-erb␤ in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erb␤ decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36, and Fabp-3 and -4). Interestingly, we observed a robust induction (>15-fold) in mRNA expression of interleukin-6, an "exerciseinduced myokine" that regulates energy expenditure and inflammation. Furthermore, we observed the dramatic repression (>20-fold) of myostatin mRNA, another myokine that is a negative regulator of muscle hypertrophy and hyperplasia that impacts on body fat accumulation. This study implicates Rev-erb␤ in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erb␤ may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth. Members of the nuclear receptor (NR)1 superfamily bind to specific DNA elements and function as transcriptional regulators (1, 2). In addition to the ligand-activated NRs, many members within this superfamily have no known ligand, and are referred to as "orphan NRs" (3). The orphan receptor Rev-erb␤ (NR1D2, also known as Rev-erb␣-related receptor, RVR) belongs to the family of "Reverbs" that also contain Rev-erb␣ (4, 5). The primary structure of these two receptors together with retinoic acid-related orphan receptor-␣ (ROR␣) and the Drosophila orphan receptor, E75A, is very similar especially in the DNA-binding domain and the putative ligand-binding domain (6).Two Rev-erb␤ genes have been identified; Rev-erb␤1 and Rev-erb␤2, which are alternatively spliced products of the Reverb␤ gene (7). The mRNA expression data shows that Rev-erb␤ is abundantly expressed in most tissues, although higher levels of expression are observed in skeletal muscle, brain, kidney, and liver (Refs. 4 and 8 and references therein).Rev-erb␣, Rev-erb␤, and ROR bind as monomers to the nuclear receptor half-site motif, PuGGTCA flanked 5Ј by an ATrich sequence ((A/T) 6 PuGGTCA). Although...

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“…Under this point of view, it is also interesting that PBP was found to interact with the estrogen receptor alpha (ERa), serving as a co-activator in the ER signaling and therefore suspected to be involved in breast cell tumorigenicity (13). In addition, there has also been shown that there is a regulatory link between NR1D1 and the NFKB pathway (14).…”

Section: Bodymentioning

confidence: 99%

Functional Genomic Analysis of Breast Cancer Cell Tumorigenicity Using a Novel Gene Silencing Resource

Conklin¹

2005

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Rev‐erbα upregulates NF‐κB‐responsive genes in vascular smooth muscle cells

Cited by 60 publications

References 39 publications

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Functional Genomic Analysis of Breast Cancer Cell Tumorigenicity Using a Novel Gene Silencing Resource

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