Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor δ-mediated transactivation

Krogsdam, Anne; Nielsen, Curt A F; Neve, Søren; Holst, Dorte; Helledie, Torben; Thomsen, Bo; Berthou, Christian; Mandrup, Susanne; Kristiansen, Karsten

doi:10.1042/0264-6021:3630157

Cited by 76 publications

(68 citation statements)

References 52 publications

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“…In the absence of ligand, co-repressor proteins, such as nuclear co-repressor (NCoR), link DNA-bound nuclear receptors to enzymes with histone deacetylase activity that cause chromatin condensation (15). Binding of a ligand with agonistic properties to the nuclear receptors causes a conformational change within their ligand-binding domain that results in the replacement of co-repressors by co-activator proteins, such as receptor-associated co-activator 3 (16) or PPAR␥ co-activator 1␣ (PGC-1␣) (17).…”

mentioning

confidence: 99%

The Insulin-like Growth Factor-binding Protein 1 Gene Is a Primary Target of Peroxisome Proliferator-activated Receptors

Degenhardt

Matilainen

Herzig

et al. 2006

Journal of Biological Chemistry

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Insulin-like growth factor-binding protein 1 (IGFBP-1) is a biomarker for metabolic and hyperproliferative diseases. At the same time, the nuclear receptors peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the development of both the metabolic syndrome and various cancers. Here we demonstrate, in human hepatocellular carcinoma cells and in normal mouse liver, that IGFBP-1 mRNA expression is under the primary control of PPAR ligands. We applied an improved in silico screening approach for PPAR response elements (PPREs) and identified five candidate PPREs located within 10 kb of the transcription start site (TSS) of the IGFBP-1 gene. Chromatin immunoprecipitation assays showed that, in living cells, the genomic region containing the most proximal PPRE, at position ؊1200 (relative to the TSS), preferentially associates with multiple PPAR subtypes and various other components of the transcriptional apparatus, which include their heterodimerizing partner, retinoid X receptor, as well as phosphorylated RNA polymerase II, co-repressor, co-activator, and mediator proteins. Moreover, further chromatin immunoprecipitation assays demonstrated that the TSS regions of the IGFBP-1 gene and those of the related IGFBP-2, -5, and -6, but not of IGFBP-3 and -4 genes, bind PPARs as well. We also show that these additional PPAR binding genes contain a number of candidate PPREs and that their mRNA levels respond quickly to the presence of PPAR ligands, indicating that they are also primary PPAR target genes.Lipid level dysregulation is a characteristic common to some of the most prevalent medical disorders, including obesity, cardiovascular disease, and type 2 diabetes (1). Nuclear receptor transcription factors may have important roles to play in these diseases, because many of them have lipophilic compounds as ligands, including fatty acids and their metabolic derivatives (2), which appear to be important in either the normal functioning or a role in the disease process affecting the metabolic pathways. For example, native and oxidized polyunsaturated fatty acids as well as arachidonic acid derivatives, such as prostaglandins and prostacyclins, selectively bind the nuclear receptors peroxisome proliferator-activated receptors (PPARs) 3 ␣, ␥, and ␤/␦ and stimulate their transcriptional activity (3). PPARs are prominent players in the metabolic syndrome, because they are important regulators of lipid storage and catabolism (4). However, PPARs also regulate cellular growth and differentiation and therefore have as well an impact on hyperproliferative diseases, such as cancer (5). PPAR␥ is the best characterized member of the subfamily due to its prominent role in the regulation of differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells (6, 7). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of synthetic PPAR␥ ligands, such as the thiazolidinediones rosiglitazone, troglitazone, and piogl...

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confidence: 99%

The Insulin-like Growth Factor-binding Protein 1 Gene Is a Primary Target of Peroxisome Proliferator-activated Receptors

Degenhardt

Matilainen

Herzig

et al. 2006

Journal of Biological Chemistry

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“…PPARA has high homology (w71%) in the amino acid sequence of its LBD with the PPARG-LBD (Xu et al 2002, Agostini et al 2004. Direct binding of CoRs with wild-type PPARG2 was demonstrated by GST pulldown assay (Zamir et al 1997, Krogsdam et al 2002, Stanley et al 2003, co-immunoprecipitation (Gurnell et al 2000, Yu et al 2005, gel shift assay (Lee et al 2002), and an in vitro pulldown assay with RXR-PPARG2 heterodimers on PPREs (Krogsdam et al 2002). Using a ChIP assay, Guan et al (2005) showed that, in adipocytes without the addition of an exogenous ligand, PPARG2 molecules associated with CoRs are present in PPREs in the promoter region of the glycerol kinase gene .…”

Section: Discussionmentioning

confidence: 99%

“…The interaction of CoRs with unliganded PPARG2-LBD has been demonstrated in vitro (Zamir et al 1997, Krogsdam et al 2002, Lee et al 2002, Stanley et al 2003 and in vivo (Gurnell et al 2000, Wang et al 2004, Yu et al 2005. RNA interference assays against the CoR genes , Yu et al 2005 and chromatin immunoprecipitation assays (ChIP) suggest that PPARG2 associates with CoR in vivo and suppresses the basal transcriptional activity of PPARG2-target genes including glycerol kinase , oxidized low-density lipoprotein receptor 1 , aP2, and PPARG itself (Picard et al 2004).…”

Section: Introductionmentioning

confidence: 99%

The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

Suzuki¹,

Sasaki²,

Morita³

et al. 2010

Journal of Molecular Endocrinology

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Peroxisome proliferator-activated receptor g-2 (PPARG2) is a ligand-dependent transcriptional factor involved in the pathogenesis of insulin resistance. In the presence of a ligand, PPARG2 associates with co-activators, while it recruits co-repressors (CoRs) in the absence of a ligand. It has been reported that the interaction of liganded PPARG2 with co-activators is regulated by the amino-terminal A/B domain (NTD) via inter-domain communication. However, the role of the NTD is unknown in the case of the interaction between unliganded PPARG2 and CoRs. To elucidate this, total elimination of the influence of ligands is required, but the endogenous ligands of PPARG2 have not been fully defined. PPARG1-P467L, a naturally occurring mutant of PPARG1, was identified in a patient with severe insulin resistance. Reflecting its very low affinity for various ligands, this mutant does not have transcriptional activity in the PPAR response element, but exhibits dominant negative effects (DNEs) on liganded wild-type PPARG2-mediated transactivation. Using the corresponding PPARG2 mutant, PPARG2-P495L, we evaluated the role of the NTD in the interaction between unliganded PPARG2 and CoRs. Interestingly, the DNE of PPARG2-P495L was increased by the truncation of its NTD. NTD deletion also enhanced the DNE of a chimeric receptor, PT, in which the ligand-binding domain of PPARG2 was replaced with that of thyroid hormone receptor b-1. Moreover, NTD deletion facilitated the in vitro binding of nuclear receptor CoR with wild-type PPARG2, mutant P495L, and the PT chimera (PPARG2-THRB). Inter-domain communication in PPARG2 regulates not only ligand-dependent transactivation but also ligand-independent silencing.

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“…This suggests co-repressors as general antagonists of the various stimuli inducing PPAR-mediated transactivation. Co-repressors can display different ligand selectivity: the nuclear receptor co-repressor NCoR interacted strongly with the ligand-binding domain of PPAR / , whereas interactions with the ligand-binding domains of PPAR and PPAR were significantly weaker (Krogsdam, Nielsen et al 2002). Very recently, a team of Harvard Medical School researchers has shown that PPAR is phosphorylated at Ser273 by cyclin dependent kinase 5 (CDK5) during obesity which results in deregulation of a subset of genes; including a number of key metabolic regulators, such as adipsin, the first fat cell-selective gene whose expression is altered in obesity and adiponectin, a central regulator of insulin sensitivity in vivo (Choi, Banks et al).…”

Section: Mechanism Of Ligand-independent Transrepressionmentioning

confidence: 99%

PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke

Benetti¹,

Patel²,

Collino³

2012

Advances in the Preclinical Study of Ischemic Stroke

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Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor δ-mediated transactivation

Cited by 76 publications

References 52 publications

The Insulin-like Growth Factor-binding Protein 1 Gene Is a Primary Target of Peroxisome Proliferator-activated Receptors

The Insulin-like Growth Factor-binding Protein 1 Gene Is a Primary Target of Peroxisome Proliferator-activated Receptors

The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke

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