Transcriptional ERRγ2-mediated activation is regulated by sentrin-specific proteases

2009 ◽  
Vol 419 (1) ◽  
pp. 167-176 ◽  
Author(s):  
Moritz Hentschke ◽  
Ute Süsens ◽  
Uwe Borgmeyer
Keyword(s):  
Nuclear Receptor ◽  
Mutational Analysis ◽  
Activation Function ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Specific Protease ◽  
Mobility Shift Assay ◽  
Group B

Modification with SUMOs (small ubiquitin-related modifiers) has emerged as an important means of regulating the activity of transcription factors, often by repressing their activity. The ERRγ [oestrogen receptor-related receptor γ; ERR3 or NR3B3 (nuclear receptor subfamily 3, group B, gene3)] is a constitutively active orphan nuclear receptor. A PDSM, (phosphorylation-dependent sumoylation motif) is located in the close vicinity of the N-terminally located ERRγ2-specific AF-1 (activation function-1). Its function can be replaced by an NDSM (negatively charged amino acid-dependent sumoylation motif). A mutational analysis reveals that ERRγ2 activity is modulated through sumoylation of a lysine residue at position 40, which in turn is regulated by phosphorylation. Phosphorylation at the +5 position relative to the sumoylation target is directly visualized by a high-resolution EMSA (electrophoretic mobility-shift assay). Sumoylation represses the activity of ERRγ both with and without forced expression of the PGC-1β (peroxisome-proliferator-activated receptor γ co-activator-1β). Fusion proteins of a heterologous DNA-binding domain with the ERRγ2 N-terminus demonstrate the function of the PDSM as the RF-1 (repression function-1) for the neighbouring AF-1. De-repression is achieved by co-expression of sentrin/SENP (sentrin-specific protease) family members. Together, our results demonstrate reversible phosphorylation-dependent sumoylation as a means to regulate the activity of an orphan nuclear receptor.

scholarly journals Definition of the Molecular Basis for Estrogen Receptor-Related Receptor-α-Cofactor Interactions

2007 ◽  
Vol 21 (1) ◽  
pp. 62-76 ◽  
Author(s):  
Stéphanie Gaillard ◽  
Mary A. Dwyer ◽  
Donald P. McDonnell
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Activation Function ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hormone Response Elements ◽  
Phage Libraries ◽  
Definition Of

Abstract Estrogen receptor-related receptor-α (ERRα) is an orphan nuclear receptor that does not appear to require a classical small molecule ligand to facilitate its interaction with coactivators and/or hormone response elements within target genes. Instead, the apo-receptor is capable of interacting in a constitutive manner with coactivators that stimulate transcription by acting as protein ligands. We have screened combinatorial phage libraries for peptides that selectively interact with ERRα to probe the architecture of the ERRα-coactivator pocket. In this manner, we have uncovered a fundamental difference in the mechanism by which this receptor interacts with peroxisome proliferator-activated receptor-γ coactivator-1α, as compared with members of the steroid receptor coactivator subfamily of coactivators. Our findings suggest that it may be possible to develop ERRα ligands that exhibit different pharmacological activities as a consequence of their ability to differentially regulate coactivator recruitment. In addition, these findings have implications beyond ERRα because they suggest that subtle alterations in the structure of the activation function-2 pocket within any nuclear receptor may enable differential recruitment of coactivators, an observation of notable pharmaceutical importance.

scholarly journals Small Heterodimer Partner, an Orphan Nuclear Receptor, Augments Peroxisome Proliferator-activated Receptor γ Transactivation

2001 ◽  
Vol 277 (2) ◽  
pp. 1586-1592 ◽  
Author(s):  
Hitoshi Nishizawa ◽  
Kazuya Yamagata ◽  
Iichiro Shimomura ◽  
Masahiko Takahashi ◽  
Hiroshi Kuriyama ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Peroxisome Proliferator ◽  
Orphan Nuclear Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner

scholarly journals Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor γ–Retinoid X Receptor α Coactivator

2018 ◽  
Vol 38 (9) ◽  
Author(s):  
Tali Shalom-Barak ◽  
Jaclyn Liersemann ◽  
Babak Memari ◽  
Lawrence Flechner ◽  
Caitlin E. Devor ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Activation Function ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Receptor Function ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Motifs ◽  
Transcription Cofactor ◽  
Target Activation

ABSTRACTThe nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an essential regulator of placental development. To gain deeper insights into placental PPARγ signaling, we dissected its regulation of theMuc1promoter. We find that, unlike prototypic target activation by heterodimeric receptors, which is either stimulated by or refractory to retinoid X receptor (RXR) ligands (rexinoids), the induction ofMuc1by liganded PPARγ requires RXRα but is inhibited by rexinoids. We demonstrate that this inhibition is mediated by the activation function 2 (AF2) domain of RXRα and thatMuc1activation entails altered AF2 structures of both PPARγ and RXRα. This unique regulation ofMuc1reflects specific coactivation of PPARγ-RXRα heterodimers by the transcription cofactor ligand-dependent corepressor (LCoR), corroborated by significant downregulation ofMuc1inLcor-null placentas. LCoR interacts with PPARγ and RXRα in a synergistic fashion via adjacent noncanonical protein motifs, and the AF2 domain of ligand-bound RXRα inhibits this interaction. We further identify the transcription factor Krüppel-like factor 6 (KLF6) as a critical regulator of placental development and a component ofMuc1regulation in cooperation with PPARγ, RXRα, and LCoR. Combined, these studies reveal new principles and players in nuclear receptor function in general and placental PPARγ signaling in particular.

scholarly journals Activating Effect of Benzbromarone, a Uricosuric Drug, on Peroxisome Proliferator-Activated Receptors

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Chiyoko Kunishima ◽  
Ikuo Inoue ◽  
Toshihiro Oikawa ◽  
Hiromu Nakajima ◽  
Tsugikazu Komoda ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Cultured Cells ◽  
Binding Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferation ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Western Blot Method ◽  
Gene Assay ◽  
Mobility Shift Assay

Benzbromarone, a uricosuric drug, reportedly causes hepatic hypertrophy accompanied by proliferation of peroxisomes in rats. To elucidate the mechanisms underlying induction of peroxisome proliferation by benzbromarone, we examined binding affinity for peroxisome proliferator-activated receptorα(PPARα) andγ(PPARγ), and effects on the binding activity of PPARs with peroxisome proliferation-responsive element (PPRE) and expression of the PPARs target protein. Binding affinity of benzbromarone forPPARαandPPARγwas examined by reporter gene assay. Binding activity of PPARs with PPRE was determined by electric mobility shift assay, and expression of lipoprotein lipase (LPL) and acyl-CoA synthetase (ACS) by Western blot method. Benzbromarone displayed affinity forPPARαandPPARγ, and promoted binding of PPARs to PPRE. Furthermore, cultured cells with benzbromarone added showed upregulated expression of LPL and ACS. These results suggest that benzbromarone induces peroxisome proliferation in hepatocytes by binding to PPARs, and controls expression of proteins related to lipid metabolism.

scholarly journals Peroxisome Proliferator-Activated Receptor Gamma Exacerbates Concanavalin A-Induced Liver Injury via Suppressing the Translocation of NF-κB into the Nucleus

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Yuji Ogawa ◽  
Masato Yoneda ◽  
Wataru Tomeno ◽  
Kento Imajo ◽  
Yoshiyasu Shinohara ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Peroxisome Proliferator ◽  
Con A ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
In The Wild ◽  
Mobility Shift Assay

Peroxisome proliferator-activated receptor-γ(PPARγ) has been reported to reduce inflammation and attenuate fibrosis in the liver. In this study, we investigated the effects of PPARγon the liver injury induced by 20 mg/kg Concanavalin A (Con A). The mice were administered one of the three types of PPARγligands (pioglitazone, ciglitazone, and troglitazone) for 1 week, and the serum alanine aminotransferase (ALT) levels at 20 h after Con A injection were significantly elevated in the PPARγligand-treated mice. Furthermore, the serum ALT levels after Con A injection in the PPARγhetero-knock-out mice (PPARγ+/−mice) were lower than those in the wild-type mice (WT mice). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) revealed extensive liver damage induced by Con A in the pioglitazone-treated mice. Electrophoresis mobility shift assay (EMSA) revealed that activation of translocation of nuclear factor- (NF-)κB, which is a suppressor of apoptosis, in the nucleus of the hepatocytes was suppressed in the pioglitazone-treated mice after Con A injection. In this study, we showed that PPARγexacerbated Con A-induced liver injury via suppressing the translocation of NF-κB into the nucleus, thereby inhibiting the suppression of liver cell apoptosis.

The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase

1993 ◽  
Vol 13 (2) ◽  
pp. 861-868
Author(s):  
T E Wilson ◽  
A R Mouw ◽  
C A Weaver ◽  
J Milbrandt ◽  
K L Parker
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Core Promoter ◽  
Orphan Nuclear Receptor ◽  
Recognition Sequence ◽  
Mobility Shift ◽  
Adrenocortical Cells ◽  
Gene Encoding ◽  
Adult Rat ◽  
Gel Mobility Shift

As part of its trophic action to maintain the steroidogenic capacity of adrenocortical cells, corticotropin (ACTH) increases the transcription of the cytochrome P-450 steroid hydroxylase genes, including the gene encoding steroid 21-hydroxylase (21-OHase). We previously identified several promoter elements that regulate 21-OHase gene expression in mouse Y1 adrenocortical tumor cells. One of these elements, located at nucleotide -65, closely resembles the recognition sequence of the orphan nuclear receptor NGFI-B, suggesting that NGFI-B regulates this essential steroidogenic enzyme. To explore this possibility, we first used in situ hybridization to demonstrate high levels of NGFI-B transcripts in the adrenal cortex of the adult rat. In cultured mouse Y1 adrenocortical cells, treatment with ACTH, the major regulator of 21-OHase transcription, rapidly increased NGFI-B expression. Gel mobility shift and DNase I footprinting experiments showed that recombinantly expressed NGFI-B interacts specifically with the 21-OHase -65 element and identified one complex formed by Y1 extracts and the 21-OHase -65 element that contains NGFI-B. Expression of NGFI-B significantly augmented the activity of the intact 21-OHase promoter, while mutations of the -65 element that abolish NGFI-B binding markedly diminished NGFI-B-mediated transcriptional activation. Specific mutations of NGFI-B shown previously to impair either DNA binding or transcriptional activation diminished the effect of NGFI-B coexpression on 21-OHase expression. Finally, an oligonucleotide containing the NGFI-B response element conferred ACTH response to a core promoter from the prolactin gene, showing that this element is sufficient for ACTH induction. Collectively, these results identify a cellular promoter element that is regulated by NGFI-B and implicate NGFI-B in the transcriptional induction of 21-OHase by ACTH.

scholarly journals Inhibition of Cellular Proliferation through IκB Kinase-Independent and Peroxisome Proliferator-Activated Receptor γ-Dependent Repression of Cyclin D1

2001 ◽  
Vol 21 (9) ◽  
pp. 3057-3070 ◽  
Author(s):  
Chenguang Wang ◽  
Maofu Fu ◽  
Mark D'Amico ◽  
Chris Albanese ◽  
Jian-Nian Zhou ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Nuclear Receptor ◽  
Cellular Proliferation ◽  
Biological Effects ◽  
S Phase ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Iκb Kinase ◽  
Anti Inflammatory

ABSTRACT The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARγ exerts diverse biological effects, promoting adipocyte differentiation, inhibiting tumor cellular proliferation, and regulating monocyte/macrophage and anti-inflammatory activities in vitro. In vivo studies with PPARγ ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARγ ligands on cellular proliferation. Recent findings that PPARγ ligands convey PPARγ-independent activities through IκB kinase (IKK) raises important questions about the specific mechanisms through which PPARγ ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARγ. Herein PPARγ, liganded by either natural (15d-PGJ2 and PGD2) or synthetic ligands (BRL49653 and troglitazone), selectively inhibited expression of the cyclin D1 gene. The inhibition of S-phase entry and activity of the cyclin D1-dependent serine-threonine kinase (Cdk) by 15d-PGJ2 was not observed in PPARγ-deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ2. Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPARγ but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARγ involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ2 enhanced recruitment of p300 to PPARγ but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects may improve the utility of COX2 inhibitors.

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