Kundu Pallob, Li Min, Lu Rong, Stefani Enrico, Toro Ligia
Department of Anesthesiology, University of California, Los Angeles, CA 90095, USA; Division of Plant Biology, Bose Institute, Kolkata 700054, India.
Department of Anesthesiology, University of California, Los Angeles, CA 90095, USA.
Mol Cell Endocrinol. 2015 Feb 5;401:202-12. doi: 10.1016/j.mce.2014.11.001. Epub 2014 Nov 7.
Estrogen receptor α (ERα) mediates estrogen diverse actions on tissues. ERα gene has eight constitutively expressing exons and is known to have multiple isoforms generated by alternative initiation of transcription and splicing events including exon skipping. We have discovered two novel exons inserted between exon 5 and 6 of rat ERα that can add independently or in tandem 18 and 14 amino acids to the estrogen binding/activator function 2 domain of the receptor. Their transcript expression is three to six fold higher in heart compared to brain, aorta, liver, ovary and uterus. In heart, the new variants increased ~2 fold with animal growth from prenatal to adulthood, and had a minor increment in aged animals (28 months). Inclusion of these exons yields a receptor with practically no binding capacity for estrogen and reduced dimerization. The new variants show nuclear localization but are less efficient in binding to estrogen responsive elements (EREs) and failed to transcriptionally activate promoters containing EREs (mSlo, KCNE2). Thus, the new variants can regulate the wild-type receptor function and may contribute to the regulatory action of estrogen, especially in the maturing heart where they are more abundant.
雌激素受体α（ERα）介导雌激素对组织的多种作用。ERα基因有八个组成型表达外显子，已知通过转录起始和剪接事件（包括外显子跳跃）的替代产生多种异构体。我们在大鼠ERα的外显子5和6之间发现了两个新的外显子，它们可以独立或串联地在受体的雌激素结合/激活功能2结构域中添加18和14个氨基酸。与脑、主动脉、肝脏、卵巢和子宫相比，它们在心脏中的转录表达高3至6倍。在心脏中，随着动物从产前到成年的生长，新变体增加了约2倍，而在老年动物（28个月）中增加较少。包含这些外显子会产生一种对雌激素几乎没有结合能力且二聚化减少的受体。新变体显示出核定位，但与雌激素反应元件（ERE）的结合效率较低，并且未能转录激活含有ERE的启动子（mSlo、KCNE2）。因此，新变体可以调节野生型受体功能，并可能有助于雌激素的调节作用，尤其是在它们更丰富的成熟心脏中。
