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The Modulator of Nongenomic Actions of the Estrogen Receptor (MNAR) Regulates Transcription-Independent Androgen Receptor-Mediated Signaling: Evidence that MNAR Participates in G Protein-Regulated Meiosis in Xenopus laevis Oocytes

Department of Obstetrics and Gynecology (D.H.), Division of Reproductive Endocrinology, Department of Internal Medicine (S.N.W., L.B.L., M.R., S.R.H.), Division of Endocrinology and Metabolism; and Department of Pharmacology (S.R.H.), University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8857

Address all correspondence and requests for reprints to: Stephen R. Hammes, Department of Internal Medicine, Division of Endocrinology and Metabolism, Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: stephen.hammes{at}utsouthwestern.edu.

Classical steroid receptors mediate many transcription-independent (nongenomic) steroid responses in vitro, including activation of Src and G proteins. Estrogen-triggered activation of Src can be regulated by the modulator of nongenomic actions of the estrogen receptor (MNAR), which binds to estrogen receptors and Src to create a signaling complex. In contrast, the mechanisms regulating steroid-induced G protein activation are not known, nor are the physiologic responses mediated by MNAR. These studies demonstrate that MNAR regulates the biologically relevant process of meiosis in Xenopus laevis oocytes. MNAR was located throughout oocytes, and reduction of its expression by RNA interference markedly enhanced testosterone-triggered maturation and activation of MAPK. Additionally, Xenopus MNAR augmented androgen receptor (AR)-mediated transcription in CV1 cells through activation of Src. MNAR and AR coimmunoprecipitated as a complex involving the LXXLL-rich segment of MNAR and the ligand binding domain of AR. MNAR and Gß also precipitated together, with the same region of MNAR being important for this interaction. Finally, reduction of MNAR expression decreased Gß-mediated signaling in oocytes. MNAR therefore appears to participate in maintaining meiotic arrest, perhaps by directly enhancing Gß-mediated inhibition of meiosis. Androgen binding to AR might then release this inhibition, allowing maturation to occur. Thus, MNAR may augment multiple nongenomic signals, depending upon the context and cell type in which it is expressed.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   PELP1

Ligands:   Dihydrotestosterone

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