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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/E1047    most recent 90429.2008v1 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 Google Scholar Google Scholar Articles by Kayahara, M. Articles by Ray, D. W. Search for Related Content PubMed PubMed Citation Articles by Kayahara, M. Articles by Ray, D. W.

MNAR functionally interacts with both NH₂- and COOH-terminal GR domains to modulate transactivation

Faculty of Medical and Human Sciences, ¹Centre for Molecular Medicine and ²Department of Cardiovascular Sciences, School of Clinical and Laboratory Sciences, University of Manchester, Manchester, United Kingdom; and ³Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas

Submitted 9 May 2008 ; accepted in final form 30 July 2008

Glucocorticoids are potent anti-inflammatory agents, acting through the glucocorticoid receptor (GR) to regulate target gene transcription. However, GR may also exert acute effects, including activation of signaling kinases such as c-Src and protein kinase B, possibly via the scaffold protein, modulator of nongenomic action of the estrogen receptor (MNAR). MNAR inhibited GR transactivation in A549 cells, but in HEK293 cells there was a ligand concentration-dependent biphasic effect. Transactivation driven by low ligand concentrations was inhibited by MNAR expression, whereas higher ligand concentrations were potentiating. Further analysis revealed that MNAR inhibited transactivation by the ligand-independent activation function (AF)1 but potentiated the COOH-terminal AF2 domain. The effect of MNAR was independent of c-Src activity, demonstrated by inhibitors and c-Src knockdown studies. In support of the role of MNAR in modulating GR transactivation, coimmunoprecipitation studies showed interaction between MNAR and GR in the nucleus but not the cytoplasm. Furthermore, MNAR and c-Src were also found to physically interact in the nucleus. Immunofluorescence studies showed MNAR to be predominantly a nuclear protein, with significant colocalization with GR. Deletion studies revealed that MNAR 884-1130 was coimmunoprecipitated with GR, and furthermore this fragment inhibited GR transactivation function when overexpressed. In addition, MNAR 1-400, which contains multiple LxxLL motifs, also inhibited GR transactivation. Taken together, MNAR interacts with GR in the nucleus but not cytoplasm and regulates GR transactivation in a complex manner depending on cell type. MNAR is capable of regulating both AF1 and AF2 functions of the GR independently. MNAR expression is likely to mediate important cell variation in glucocorticoid responsiveness, in a c-Src-independent mechanism.

glucocorticoid receptor; modulator of nongenomic action of the estrogen receptor; c-Src; glucocorticoid