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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.

ABSTRACT: 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 Gbeta also precipitated together, with the same region of MNAR being important for this interaction. Finally, reduction of MNAR expression decreased Gbetagamma-mediated signaling in oocytes. MNAR therefore appears to participate in maintaining meiotic arrest, perhaps by directly enhancing Gbetagamma-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.

SUBMITTER: Haas D

PROVIDER: S-EPMC1482432 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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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.

Haas Derek D White Stacy N SN Lutz Lindsey B LB Rasar Melissa M Hammes Stephen R SR

Molecular endocrinology (Baltimore, Md.) 20050414 8

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 ...[more]

PMID: 15831520

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Project description:Formyl-methionine-containing peptides (e.g. fMet-Leu-Phe) stimulate a variety of neutrophil functions by interacting with specific cell surface receptors which are coupled via G-proteins to stimulation of phospholipase C. Two markedly distinct cDNAs coding for formyl peptide receptors have recently been isolated from a rabbit and a human cDNA library respectively. To examine the hitherto unknown signal transduction properties of the formyl peptide receptor encoded by the human cDNA, we have used the PCR to clone this cDNA from poly(A)+ RNA of myeloid differentiated human leukaemia (HL-60) cells, and have injected the cDNA-derived receptor cRNA into Xenopus laevis oocytes. Receptor activity was determined electrophysiologically by measuring the agonist-dependent opening of intracellular Ca2+ concentration ([Ca2+]i)-independent Cl- channels. Injection of pure formyl peptide receptor cRNA did not lead to peptide-dependent changes in membrane current. In contrast, marked alterations of membrane current were observed in response to formyl peptides when the receptor cRNA was supplemented with poly(A)+ RNA isolated from undifferentiated HL-60 cells. Injection of the latter RNA did not lead to formyl-peptide-dependent alterations of membrane current. Binding studies using a radioiodinated formyl peptide revealed that injection of formyl peptide receptor cRNA alone led to expression of the formyl peptide receptor on the oocyte surface, and that co-injection of poly(A)+ RNA from undifferentiated HL-60 cells did not alter the level of receptor expression. Size fractionation of poly(A)+ RNA from undifferentiated HL-60 cells showed that the mRNA required to complement formyl-peptide-dependent signal transduction in oocytes had a size of approx. 3-3.5 kb. These results strongly suggest that the human formyl peptide receptor requires a specific cofactor(s), which is lacking in Xenopus oocytes but is present in undifferentiated HL-60 cells, to activate the second messenger pathway in oocytes. Identification of this factor will provide important information about the molecular mechanisms by which G-protein-coupled granulocyte-activating receptors stimulate phospholipase C.

Dataset Information

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.

Publications

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.

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