HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 14, 9118-9126, April 7, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/14/9118    most recent M509339200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kino, T. Articles by Segars, J. H. Search for Related Content PubMed PubMed Citation Articles by Kino, T. Articles by Segars, J. H. Social Bookmarking                      What's this?

Rho Family Guanine Nucleotide Exchange Factor Brx Couples Extracellular Signals to the Glucocorticoid Signaling System^*

Tomoshige Kino¹, Emanuel Souvatzoglou, Evangelia Charmandari, Takamasa Ichijo, Paul Driggers, Chantal Mayers, Anton Alatsatianos, Irini Manoli^¶, Heiner Westphal^||, George P. Chrousos^**, and James H. Segars

From the Pediatric Endocrinology Section, Reproductive Biology and Medicine Branch, NICHD, National Institutes of Health, ^¶National Center for Complementary and Alternative Medicine, and ^||Laboratory of Mammalian Genes and Development, NICHD, National Institutes of Health, Bethesda Maryland 20892, Department of Obstetrics and Gynecology, Uniformed Services University of Health Sciences, Bethesda, Maryland 20814, and ^**First Department of Pediatrics, Athens University Medical School, Athens 11527, Greece

Glucocorticoids regulate many crucial biologic functions through their cytoplasmic/nuclear glucocorticoid receptors (GR). Excess, deficiency, or alteration in tissue sensitivity to glucocorticoids has been associated with major causes of human morbidity and mortality. Brx, a cytoplasmic Rho family guanine nucleotide exchange factor, binds to and influences the activity of several nuclear hormone receptors. We examined the functional and molecular interactions between GR and Brx. The glucocorticoid sensitivity of lymphocytes obtained from mice haplo-insufficient for Brx was significantly decreased. Conversely, GR-mediated transcriptional activity of a glucocorticoid response element (GRE)-mediated glucocorticoid-responsive promoter was enhanced by Brx in a guanine nucleotide exchange factor domain-dependent fashion. Brx interacted with GR, forming a ternary complex with RhoA. In a chromatin immunoprecipitation assay, Brx and RhoA were co-precipitated with GREs only in the presence of ligand-activated GR. Extracellularly administered lysophosphatidic acid, which activates its signaling cascade through a specific membrane GTP-binding protein (G-protein)-coupled receptor in a G-protein ₁₃-, Brx-, and RhoA-dependent fashion, enhanced GR transcriptional activity, whereas depletion of endogenous Brx attenuated this effect. These findings suggest that glucocorticoid signaling and, hence, the tissue sensitivity to glucocorticoids, may be coupled to extracellular signals via Brx and small G-proteins. Nuclear Brx might act as a local GRE-GR-transcriptosome activator by mediating the effect of small G-proteins on glucocorticoid-regulated genes.

Received for publication, August 24, 2005 , and in revised form, December 30, 2005.

^* This study was funded in part by NICHD, National Institutes of Health, Bethesda, MD. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Pediatric Endocrinology Section, Reproductive Biology and Medicine Branch, NICHD, National Institutes of Health, Bldg. 10, Clinical Research Center, Rm. 1-3140, 10 Center Dr., MSC 1109, Bethesda, MD 20892-1109. Tel.: 301-496-6417; Fax: 301-402-0884; E-mail: kinot{at}mail.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. S. Lyons, S. Rao, W. Balkan, J. Faysal, C. A. Maiorino, and K. L. Burnstein Ligand-Independent Activation of Androgen Receptors by Rho GTPase Signaling in Prostate Cancer Mol. Endocrinol., March 1, 2008; 22(3): 597 - 608. [Abstract] [Full Text] [PDF]

				S. El Marzouk, J. R Schultz-Norton, V. S Likhite, I. X McLeod, J. R Yates, and A. M Nardulli Rho GDP dissociation inhibitor {alpha} interacts with estrogen receptor {alpha} and influences estrogen responsiveness J. Mol. Endocrinol., October 1, 2007; 39(4): 249 - 259. [Abstract] [Full Text] [PDF]