A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity.

A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Research Abstract Details 

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A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Abstract Text:

Michael Schupp,Joshua C Curtin,Roy J Kim,Andrew N Billin,Mitchell A Lazar,

Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor alpha (RARalpha), is used to treat leukemia. Another RARalpha ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARalpha function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARgamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARgamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARgamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARalpha agonist or by depleting cells of RARalpha, indicating that PPARgamma activation was not related to RARalpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARgamma, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARgamma agonist as well as an RARalpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.

A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Publishing Authors By Initials

M Schupp,JC Curtin,RJ Kim,AN Billin,MA Lazar,

For similar organic chemicals: hydrocarbons: hydrocarbons, cyclic: hydrocarbons, aromatic: polycyclic hydrocarbons, aromatic: naphthalenes: tetrahydronaphthalenes research abstracts see: organic chemicals: hydrocarbons: hydrocarbons, cyclic: hydrocarbons, aromatic: polycyclic hydrocarbons, aromatic: naphthalenes: tetrahydronaphthalenes research

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A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular pharmacology

VOLUME: 71

Page Numbers: 1251-7

Journal Abbreviation:

ISSN: 0026-895X

DAY: 8

MONTH: 02

YEAR: 2007

A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Information

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LANGUAGE: eng

NlmUniqueID: 35623

A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Keywords Mesh Terms:

KEYWORDS: Tetrahydronaphthalenes

MESH TERMS: pharmacology

Chemical & Substance for Abstract: A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Information

Substance Name: Ro 41-5253

Registry Number: 144092-31-9

Grant and Affiliation Information for A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity.

AFFILIATION: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6149, USA.

Country: United States

AGENCY: United States NIDA

GRANT: R01-DA49780

ACRONYM: DA

MEDLINETA: Mol Pharmacol

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