30 results match your criteria co-regulator peroxisome

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Mitochondrial Dysfunction in Huntington's disease: Pathogenesis and Therapeutic Opportunities.

Curr Drug Targets 2021 Feb 23. Epub 2021 Feb 23.

Department of Pharmacy, Faculty of Pharmacy, University of Oradea. Romania.

Huntington's disease (HD) is prototypical neurodegenerative disease, preferentially disrupts the neurons of striatum and cor-tex. Progressive motor dysfunctions, psychiatric disturbances, behavioural impairments and cognitive decline are the clinical symptoms of HD progression. The disease occurs due to, expanded CAG repeats in exon 1 of huntingtin protein (mHtt) causing its aggregation. Read More

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February 2021

Effect of PGC1-beta ablation on myonuclear organisation.

J Muscle Res Cell Motil 2019 12;40(3-4):335-341

Faculty of Life Sciences & Medicine, School of Basic and Medical Biosciences, Centre of Human and Applied Physiological Sciences, King's College London, London, UK.

Skeletal muscle fibres are large, elongated multinucleated cells. Each nucleus within a myofibre is responsible for generating gene products for a finite volume of cytoplasm-the myonuclear domain (MND). Variation in MND sizes during atrophy, hypertrophy and disease states, are common. Read More

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December 2019

Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.

J Med Chem 2019 02 7;62(4):2008-2023. Epub 2019 Feb 7.

Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.

Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. Read More

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February 2019

PGC-1β modulates statin-associated myotoxicity in mice.

Arch Toxicol 2019 02 3;93(2):487-504. Epub 2018 Dec 3.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031, Basel, Switzerland.

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1β expression in human and rat skeletal muscle, suggesting that PGC-1β may play a role in statin-induced myopathy. Read More

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February 2019

PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.

Sci Rep 2018 09 24;8(1):14290. Epub 2018 Sep 24.

Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.

Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. Read More

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September 2018

PGC1α regulates ACMSD expression through cooperation with HNF4α.

Amino Acids 2018 Dec 19;50(12):1769-1773. Epub 2018 Sep 19.

Laboratory of Food and Nutrition, Division of Applied Biochemistry, Graduate School of Horticulture, Chiba University, 648 Matsudo, Matsudo, Chiba, 271-8510, Japan.

ACMSD is a tryptophan metabolic key enzyme. HNF4α regulates the transcription of some energy-metabolic enzymes by cooperating with PGC1α, a major transcriptional co-regulator involved in energy metabolism. In this study, we investigated the involvement of PGC1α in Acmsd expression through cooperation with HNF4α. Read More

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December 2018

Defining a conformational ensemble that directs activation of PPARγ.

Nat Commun 2018 05 4;9(1):1794. Epub 2018 May 4.

Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, MT, 59812, USA.

The nuclear receptor ligand-binding domain (LBD) is a highly dynamic entity. Crystal structures have defined multiple low-energy LBD structural conformations of the activation function-2 (AF-2) co-regulator-binding surface, yet it remains unclear how ligand binding influences the number and population of conformations within the AF-2 structural ensemble. Here, we present a nuclear receptor co-regulator-binding surface structural ensemble in solution, viewed through the lens of fluorine-19 (F) nuclear magnetic resonance (NMR) and molecular simulations, and the response of this ensemble to ligands, co-regulator peptides and heterodimerization. Read More

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Glia Maturation Factor Dependent Inhibition of Mitochondrial PGC-1α Triggers Oxidative Stress-Mediated Apoptosis in N27 Rat Dopaminergic Neuronal Cells.

Mol Neurobiol 2018 Sep 30;55(9):7132-7152. Epub 2018 Jan 30.

Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting over five million individuals worldwide. The exact molecular events underlying PD pathogenesis are still not clearly known. Glia maturation factor (GMF), a neuroinflammatory protein in the brain plays an important role in the pathogenesis of PD. Read More

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September 2018

The Transcription Factor IRF6 Co-Represses PPARγ-Mediated Cytoprotection in Ischemic Cerebrovascular Endothelial Cells.

Sci Rep 2017 05 19;7(1):2150. Epub 2017 May 19.

Department of Gerontology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPARγ's co-regulators during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPARγ co-regulator that directly binds to and suppresses PPARγ activity in murine cerebrovascular endothelial cells. Read More

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Oxidative and energetic stresses mediate beta-cell dysfunction induced by PGC-1α.

Diabetes Metab 2018 Feb 1;44(1):45-54. Epub 2017 Mar 1.

INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Sorbonne Université, UPMC, University Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address:

Aim: Alteration of functional beta-cell mass in adults can be programmed by adverse events during fetal life. Previously, it was demonstrated that high glucocorticoid (GC) levels during fetal life participate in this programming by inhibition of beta-cell development. More specifically, GC levels stimulate expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a transcriptional co-regulator of the GC receptor (GR), which per se impairs beta-cell mass and function when overexpressed. Read More

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February 2018

Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy).

Hum Mol Genet 2016 06 22;25(11):2194-2207. Epub 2016 Mar 22.

Department of Neurology, David Geffen School of Medicine Center for Duchenne Muscular Dystrophy

Limb girdle muscular dystrophy 2A is due to loss-of-function mutations in the Calpain 3 (CAPN3) gene. Our previous data suggest that CAPN3 helps to maintain the integrity of the triad complex in skeletal muscle. In Capn3 knock-out mice (C3KO), Ca release and Ca/calmodulin kinase II (CaMKII) signaling are attenuated. Read More

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The metabolic co-regulator PGC1α suppresses prostate cancer metastasis.

Nat Cell Biol 2016 06 23;18(6):645-656. Epub 2016 May 23.

Tumour Plasticity Team, Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. Read More

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Increased glucose utilization and decreased fatty acid metabolism in myotubes from Glmp(gt/gt) mice.

Arch Physiol Biochem 2016 27;122(1):36-45. Epub 2016 Jan 27.

b Department of Pharmaceutical Biosciences , School of Pharmacy, University of Oslo , Oslo , Norway , and.

Glycosylated lysosomal membrane protein (GLMP) has been reported to enhance the expression from a peroxisome proliferator-activated receptor alpha (PPARα) responsive promoter, but also to be an integral lysosomal membrane protein. Using myotubes established from wild-type and Glmp(gt/gt) mice, the importance of GLMP in skeletal muscle was examined. Glmp(gt/gt) myotubes expressed a more glycolytic phenotype than wild-type myotubes. Read More

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October 2016

Complex Coordination of Cell Plasticity by a PGC-1α-controlled Transcriptional Network in Skeletal Muscle.

Front Physiol 2015 9;6:325. Epub 2015 Nov 9.

Biozentrum, University of Basel Basel, Switzerland.

Skeletal muscle cells exhibit an enormous plastic capacity in order to adapt to external stimuli. Even though our overall understanding of the molecular mechanisms that underlie phenotypic changes in skeletal muscle cells remains poor, several factors involved in the regulation and coordination of relevant transcriptional programs have been identified in recent years. For example, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a central regulatory nexus in the adaptation of muscle to endurance training. Read More

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November 2015

SIRT1 is a direct coactivator of thyroid hormone receptor β1 with gene-specific actions.

PLoS One 2013 26;8(7):e70097. Epub 2013 Jul 26.

Genomic Medicine Program, Methodist Hospital Research Institute, Houston, Texas, USA.

Sirtuin 1 (SIRT1) NAD(+)-dependent deacetylase regulates energy metabolism by modulating expression of genes involved in gluconeogenesis and other liver fasting responses. While many effects of SIRT1 on gene expression are mediated by deacetylation and activation of peroxisome proliferator activated receptor coactivator α (PGC-1α), SIRT1 also binds directly to DNA bound transcription factors, including nuclear receptors (NRs), to modulate their activity. Since thyroid hormone receptor β1 (TRβ1) regulates several SIRT1 target genes in liver and interacts with PGC-1α, we hypothesized that SIRT1 may influence TRβ1. Read More

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KLF11 mediates PPARγ cerebrovascular protection in ischaemic stroke.

Brain 2013 Apr 12;136(Pt 4):1274-87. Epub 2013 Feb 12.

Cardiovascular Centre, Department of Internal Medicine, University of Michigan Medical Centre, NCRC Bld 26, Rm 361S, 2800 Plymouth Rd, Ann Arbor, MI 48109, USA.

Peroxisome proliferator-activated receptor gamma (PPARγ) is emerging as a major regulator in neurological diseases. However, the role of (PPARγ) and its co-regulators in cerebrovascular endothelial dysfunction after stroke is unclear. Here, we have demonstrated that (PPARγ) activation by pioglitazone significantly inhibited both oxygen-glucose deprivation-induced cerebral vascular endothelial cell death and middle cerebral artery occlusion-triggered cerebrovascular damage. Read More

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Contributions of peroxisome proliferator-activated receptor β/δ to skin health and disease.

Biomol Concepts 2013 Feb;4(1):53-64

Among the three peroxisome proliferator-activated receptor (PPAR) transcription factors, PPARβ/δ is the isotype with the broadest expression pattern. In fact, the expression of PPARβ/δ is ubiquitous, albeit at levels that are tightly regulated. Herein, we reviewed its multiple functions in skin health and disease. Read More

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February 2013

DP97, a DEAD box DNA/RNA helicase, is a target gene-selective co-regulator of the constitutive androstane receptor.

Biochem Biophys Res Commun 2012 Sep 13;426(1):38-42. Epub 2012 Aug 13.

Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.

The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that DP97, a member of the DEAD box DNA/RNA helicase protein family, is a novel CAR-interacting protein. Using HepG2 cells expressing human CAR in the presence of tetracycline, we showed that knockdown of DP97 with small interfering RNAs suppressed tetracycline-inducible mRNA expression of CYP2B6 and UGT1A1 but not CYP3A4. Read More

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September 2012

Transducer of regulated CREB-binding proteins (TORCs) transcription and function is impaired in Huntington's disease.

Hum Mol Genet 2012 Aug 15;21(15):3474-88. Epub 2012 May 15.

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA.

Huntington's disease (HD) is an incurable neurological disorder caused by an abnormal glutamine repeat expansion in the huntingtin (Htt) protein. In the present studies, we investigated the role of Transducers of Regulated cAMP response element-binding (CREB) protein activity (TORCs) in HD, since TORCs play an important role in the expression of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), whose expression is impaired in HD. We found significantly decreased TORC1 expression levels in STHdhQ111 cells expressing mutant Htt, in the striatum of NLS-N171-82Q, R6/2 and HdhQ111 HD transgenic mice and in postmortem striatal tissue from HD patients. Read More

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Antioxidants in Huntington's disease.

Biochim Biophys Acta 2012 May 23;1822(5):664-74. Epub 2011 Nov 23.

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA.

Huntington's disease (HD) is a prototypical neurodegenerative disease in which there is selective neuronal degeneration, which leads to progressive disability, manifesting itself as a movement disorder, with both psychiatric and cognitive impairment. The disease is caused by a cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene, which causes an expanded polyglutamine repeat in the huntingtin protein, resulting in a protein with a novel gain of function. The mutant huntingtin protein causes neuronal dysfunction and eventual cell death in which transcriptional impairment, excitotoxicity, oxidative damage, inflammation, apoptosis and mitochondrial dysfunction are all implicated. Read More

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Dietary lipid during the transition period to manipulate subcutaneous adipose tissue peroxisome proliferator-activated receptor-γ co-regulator and target gene expression.

J Dairy Sci 2011 Dec;94(12):5913-25

Departamento Clínicas Veterinária, Universidade Federal de Pelotas, NUPEEC, Campus Universitário, 96010-900 Pelotas, Rio Grande do Sul, Brazil.

Objectives were to determine adipose tissue mRNA expression of peroxisome proliferator-activated receptor (PPAR)γ co-regulators, target enzymes and transcription regulators, inflammation-related genes, and adipokines in response to dietary long-chain fatty acids (LCFA). From -21 through 10 d relative to parturition cows were fed no supplemental LCFA (control), saturated LCFA (SFAT; mainly 16:0 and 18:0), or fish oil (FO). Lipid was fed at 250 g/d prepartum or approximately 1. Read More

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December 2011

Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons.

Development 2010 Oct 15;137(20):3489-99. Epub 2010 Sep 15.

Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.

Mammalian limb and trunk skeletal muscles are composed of muscle fibers that differ in contractile and molecular properties. They are commonly divided into four categories according to the myosin heavy chain that they express: I, IIA, IIX and IIB, ranging from slowest to fastest. Individual motor axons innervate tens of muscle fibers, nearly all of which are of the same type. Read More

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October 2010

The neurogenic basic helix-loop-helix transcription factor NeuroD6 confers tolerance to oxidative stress by triggering an antioxidant response and sustaining the mitochondrial biomass.

ASN Neuro 2010 May 24;2(2):e00034. Epub 2010 May 24.

Department of Anatomy and Regenerative Biology, George Washington University Medical Center, 2300 I Street N.W., Washington, DC 20037, U.S.A.

Preserving mitochondrial mass, bioenergetic functions and ROS (reactive oxygen species) homoeostasis is key to neuronal differentiation and survival, as mitochondria produce most of the energy in the form of ATP to execute and maintain these cellular processes. In view of our previous studies showing that NeuroD6 promotes neuronal differentiation and survival on trophic factor withdrawal, combined with its ability to stimulate the mitochondrial biomass and to trigger comprehensive antiapoptotic and molecular chaperone responses, we investigated whether NeuroD6 could concomitantly modulate the mitochondrial biomass and ROS homoeostasis on oxidative stress mediated by serum deprivation. In the present study, we report a novel role of NeuroD6 as a regulator of ROS homoeostasis, resulting in enhanced tolerance to oxidative stress. Read More

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PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress.

Cardiovasc Res 2010 Mar 10;85(4):701-10. Epub 2009 Nov 10.

Bywaters Center for Vascular Inflammation, Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.

Aims: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARdelta has an established role in metabolism, wound healing, and angiogenesis. However, little is known about its function in endothelial homeostasis. Read More

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The neurogenic basic helix-loop-helix transcription factor NeuroD6 concomitantly increases mitochondrial mass and regulates cytoskeletal organization in the early stages of neuronal differentiation.

ASN Neuro 2009 Sep 16;1(4). Epub 2009 Sep 16.

Department of Anatomy and Regenerative Biology, George Washington University Medical Center, 2300 I Street N.W., Washington, DC 20037, USA.

Mitochondria play a central role during neurogenesis by providing energy in the form of ATP for cytoskeletal remodelling, outgrowth of neuronal processes, growth cone activity and synaptic activity. However, the fundamental question of how differentiating neurons control mitochondrial biogenesis remains vastly unexplored. Since our previous studies have shown that the neurogenic bHLH (basic helix-loop-helix) transcription factor NeuroD6 is sufficient to induce differentiation of the neuronal progenitor-like PC12 cells and that it triggers expression of mitochondrial-related genes, we investigated whether NeuroD6 could modulate the mitochondrial biomass using our PC12-ND6 cellular paradigm. Read More

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September 2009

Single gene contributions: genetic variants of peroxisome proliferator-activated receptor (isoforms alpha, beta/delta and gamma) and mechanisms of dyslipidemias.

Curr Opin Lipidol 2008 Apr;19(2):106-12

Department of Obstetrics & Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore.

Purpose Of Review: Polymorphisms in peroxisome proliferator-activated receptor isoforms may be among the most important single-gene contributors to dyslipidemias, insulin resistance, and maturity-onset diabetes.

Recent Findings: Familial partial lipodystrophy is a rare but characteristic phenotype associated with carriers of peroxisome proliferator-activated receptor-gamma missense mutations. Mutant receptors are transcriptionally defective, exhibit aberrant affinity for co-regulator molecules, and can exert dominant-negative or haplo-insufficiency effects on normal peroxisome proliferator-activated receptor-gamma function. Read More

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A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene.

J Biol Chem 2006 Apr 17;281(15):10081-8. Epub 2006 Feb 17.

Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio University College of Medicine, 4209 State Route 44, Rootstown, OH 44272, USA.

Prox1, an early specific marker for developing liver and pancreas in foregut endoderm has recently been shown to interact with alpha-fetoprotein transcription factor and repress cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription. Using a yeast two-hybrid assay, we found that Prox1 strongly and specifically interacted with hepatocyte nuclear factor (HNF)4alpha, an important transactivator of the human CYP7A1 gene in bile acid synthesis and phosphoenolpyruvate carboxykinase (PEPCK) gene in gluconeogenesis. A real time PCR assay detected Prox1 mRNA expression in human primary hepatocytes and HepG2 cells. Read More

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The nuclear receptor coactivator PGC-1alpha exhibits modes of interaction with the estrogen receptor distinct from those of SRC-1.

J Mol Biol 2005 Apr;347(5):921-34

INSERM U554 Centre de Biochimie Structurale, 29 rue de Navacelles 34090, Montpellier Cedex, France.

Estrogen receptor (ER) function is mediated by multi-domain co-regulator proteins. A fluorescently labelled fragment of the human PGC-1alpha co-regulator (residues 91-408) bearing the two motifs most strongly implicated in interactions with nuclear receptors (NR box2 and NR box3), was used to characterize in vitro binding of PGC-1alpha to ER. Anisotropy measurements revealed that the affinity of this PGC-1alpha fragment for human ERalpha and beta was fairly strong in the presence of estradiol (approximately 5 nM), and that unlike a similar fragment of SRC-1 (570-780), PGC-191-408 exhibited ligand-independent interactions with ER, particularly with ERbeta (Kd approximately 30 nM). Read More

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SDP1 is a peroxisome-proliferator-activated receptor gamma 2 co-activator that binds through its SCAN domain.

Biochem J 2003 Mar;370(Pt 2):719-27

Novartis Institute for Biomedical Research, 556 Morris Ave., Summit, NJ 07901, USA.

Peroxisome-proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, play an important role in the regulation of lipid metabolism and energy homoeostasis. In a yeast two-hybrid experiment using the zinc-finger transcription factor ZNF202 as bait, we previously identified the SCAN-domain-containing protein SDP1. SDP1 shares a high degree of amino acid sequence identity with PGC-2, a previously identified PPAR gamma 2 co-activator from the mouse. Read More

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