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
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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DOI：
10.1210/me.2004-0531
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发表时间：
2005-08-01
影响因子：
--
通讯作者：
Hammes, SR
中科院分区：
文献类型：
--
作者：
Haas, D;White, SN;Hammes, SR
经典的类固醇受体在体外介导许多非基因组的转录非依赖的类固醇反应，包括激活Src和G蛋白。雌激素对Src的激活可由雌激素受体(Mnar)的非基因组作用调节剂调节，它与雌激素受体和Src结合，形成信号复合体。相比之下，调节类固醇诱导的G蛋白激活的机制尚不清楚，也不知道Mnar介导的生理反应。这些研究表明，Mnar调控非洲爪哇卵母细胞减数分裂的生物学相关过程。Mnar广泛分布于卵母细胞，通过RNA干扰降低其表达可显著增强睾酮诱导的成熟和MAPK的激活。此外，非洲爪哇还通过激活Src来增强雄激素受体(AR)在CV1细胞中的转录。MnAR和AR共免疫共沉淀为一种涉及MnAR富含LxxL1片段和AR配体结合域的复合体。Mnar和Gβ也一起沉淀，Mnar的同一区域对这种相互作用很重要。最后，Mnar表达的降低降低了卵母细胞中Gβ伽马介导的信号转导。因此，Mnar似乎参与了减数分裂停滞的维持，可能是通过直接增强Gβ伽马介导的减数分裂抑制。雄激素与AR的结合可能会释放这种抑制，使成熟发生。因此，根据表达的上下文和细胞类型，Mnar可能会增加多个非基因组信号。
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 G beta also precipitated together, with the same region of MNAR being important for this interaction. Finally, reduction of MNAR expression decreased G beta gamma-mediated signaling in oocytes. MNAR therefore appears to participate in maintaining meiotic arrest, perhaps by directly enhancing G beta gamma-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.