Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators

Molnár, Ferdinand; Matilainen, Merja; Carlberg, Carsten

doi:10.1074/jbc.m502463200

Cited by 62 publications

(63 citation statements)

References 65 publications

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“…It has previously been proposed that PPARs have high basal activity because of a ligand-independent stabilization of helix 12 in the LBD, resulting in ligand-independent coactivator association (Molnar et al, 2005). Although this could in principle explain the inverse agonistic properties of ST247, this is unlikely, because we were unable to detect changes in CBP recruitment to the ANGPTL4 gene upon ST247 treatment (data not shown).…”

Section: Discussioncontrasting

confidence: 50%

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

Naruhn

Toth²,

Adhikary³

et al. 2011

Mol Pharmacol

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Peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) is a ligand-regulated nuclear receptor with essential functions in metabolism and inflammation. We have synthesized a new derivative [methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247) structurally related to the published PPAR␤/␦ inhibitory ligand methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (GSK0660). ST247 has a higher affinity to PPAR␤/␦ than GSK0660, and at equimolar concentrations, it more efficiently 1) induces the interaction with corepressors both in vitro and in vivo, 2) inhibits the agonist-induced transcriptional activity of PPAR␤/␦, and 3) downregulates basal level expression of the peroxisome proliferator responsive element-driven PPAR␤/␦ target gene ANGPTL4. Methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (PT-S58), another high-affinity derivative from our series, also efficiently inhibits agonist-induced transcriptional activation, but in contrast to ST247, it does not enhance the interaction of PPAR␤/␦ with corepressors. PT-S58 rather prevents corepressor recruitment triggered by the inverse agonist ST247. These findings classify ST247 as an inverse agonist, whereas PT-S58 is the first pure PPAR␤/␦ antagonist described to date. It is noteworthy that ST247 and PT-S58 are also effective on PPREindependent functions of PPAR␤/␦: in monocytic cells, both ligands modulate expression of the activation marker CCL2 in the opposite direction as an established PPAR␤/␦ agonist. The possibility to differentially modulate specific functions of PPAR␤/␦ makes these novel compounds invaluable tools to advance our understanding of PPAR␤/␦ biology.

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Section: Discussioncontrasting

confidence: 50%

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

Naruhn

Toth²,

Adhikary³

et al. 2011

Mol Pharmacol

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“…However, the AF2 of the ligand binding domain (LBD) may also contribute to the ligand-independent transactivation. Helix 12 has been reported to be in an "agonist position" in crystal structures of apo-PPAR␥LBD (46), and recent investigations indicated that this is due to the stabilization of helix 12 in the agonist position by specific charged amino acids in the LBD (42). In keeping with this, PPAR␥LBD has recently been shown to interact with CBP/p300 (33) as well as p160 CoA (42) in the absence of ligands.…”

Section: Discussionmentioning

confidence: 54%

“…Helix 12 has been reported to be in an "agonist position" in crystal structures of apo-PPAR␥LBD (46), and recent investigations indicated that this is due to the stabilization of helix 12 in the agonist position by specific charged amino acids in the LBD (42). In keeping with this, PPAR␥LBD has recently been shown to interact with CBP/p300 (33) as well as p160 CoA (42) in the absence of ligands. Presence of a synthetic ligand further induces stabilization of helix 12, thereby leading to an increased interaction with coactivators (42).…”

Section: Discussionmentioning

confidence: 54%

“…In keeping with this, PPAR␥LBD has recently been shown to interact with CBP/p300 (33) as well as p160 CoA (42) in the absence of ligands. Presence of a synthetic ligand further induces stabilization of helix 12, thereby leading to an increased interaction with coactivators (42). Future investigations in our adenoviral system with truncated and mutated PPARs will help clarify whether the ligand-independent transactivation of endogenous genes is due primarily to the AF1 or the AF2 function and whether these effects are promoter specific.…”

Section: Discussionmentioning

confidence: 83%

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Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery

Nielsen

Grøntved

Stunnenberg

et al. 2006

Molecular and Cellular Biology

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Investigations of the molecular events involved in activation of genomic target genes by peroxisome proliferator-activated receptors (PPARs) have been hampered by the inability to establish a clean on/off state of the receptor in living cells. Here we show that the combination of adenoviral delivery and chromatin immunoprecipitation (ChIP) is ideal for dissecting these mechanisms. Adenoviral delivery of PPARs leads to a rapid and synchronous expression of the PPAR subtypes, establishment of transcriptional active complexes at genomic loci, and immediate activation of even silent target genes. We demonstrate that PPAR␥2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPAR␥2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (␣, ␥, and ␤/␦), we show that the subtypes have very different abilities to gain access to target sites and that in general the genomic occupancy correlates with the ability to activate the corresponding target gene. In addition, the specificity and potency of activation by PPAR subtypes are highly dependent on the cell type. Thus, PPAR subtype-specific activation of genomic target genes involves an intricate interplay between the properties of the subtype-and cell-type-specific settings at the individual target loci.

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“…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). These co-activators link ligand-activated nuclear receptors to enzymes displaying histone acetyltransferase activity that cause chromatin relaxation and thereby reverse the action of unliganded nuclear receptors.…”

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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Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators

Abstract: Lipid homeostasis is controlled by various nuclear receptors (NRs), including the peroxisome proliferatoractivated receptors (PPAR␣,␦

Cited by 62 publications

References 65 publications

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery

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

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