Along with sodium/calcium (Ca2+) exchangers, plasma membrane Ca2+ ATPases (ATP2Bs) are main regulators of intracellular Ca2+ levels. There are four ATP2B paralogs encoded by four different genes. Atp2b2 encodes the protein pump with the fastest activation, ATP2B2. In mice, the Atp2b2 transcript has several alternate transcriptional start site variants: α, β, µ and δ. These variants are expressed in developmental and tissue specific manners. The α and β Atp2b2 transcripts are equally expressed in the brain. αAtp2b2 is the only transcript found in the outer hair cells of young mice (Silverstein RS, Tempel BL. in Neuroscience 141:245–257, 2006). Mutations in the coding region of the mouse Atp2b2 gene indicate a narrow window for tolerated dysfunction of the ATP2B2 protein, specifically in the auditory system. This highlights the necessity of tight regulation of this gene for normal cell physiology. Although ATP2Bs are important regulators of Ca2+ in many cell types, little is known about their transcriptional regulation. This study identifies the proximal promoter of the αAtp2b2 transcript. Further investigations indicate that ATOH1 and EGR1 modulate promoter activity. Additionally, we report that EGR1 increases endogenous expression of Atp2b2 transcript in two cell lines. Electrophoretic mobility shift assays (EMSA) indicate that EGR1 binds to a specific site in the CpG island of the αAtp2b2 promoter. This study furthers our understanding of Atp2b2 regulation by: (I) elucidating transcriptional regulatory mechanisms for Atp2b2, and (II) identifying transcription factors that modulate expression of Atp2b2 in the brain and peripheral auditory system and (III) allows for future studies modulating gene expression of Atp2b2.

中文翻译：

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早期生长反应蛋白 1 调节 α-质膜钙 ATP 酶 2 的启动子活性，α-质膜钙 ATP 酶 2 是大脑和听觉系统中的主要钙泵。

与钠/钙 (Ca2+) 交换器一样，质膜 Ca2+ ATP 酶 (ATP2B) 是细胞内 Ca2+ 水平的主要调节因子。有四种 ATP2B 旁系同源物，由四种不同的基因编码。Atp2b2 编码激活速度最快的蛋白泵 ATP2B2。在小鼠中，Atp2b2 转录物具有几种替代转录起始位点变体：α、β、μ 和 δ。这些变异以发育和组织特异性方式表达。α 和 β Atp2b2 转录本在大脑中同等表达。αAtp2b2 是在年轻小鼠的外毛细胞中发现的唯一转录本（Silverstein RS, Tempel BL. in Neuroscience 141:245–257, 2006）。小鼠 Atp2b2 基因编码区的突变表明 ATP2B2 蛋白的耐受功能障碍的窗口很窄，特别是在听觉系统中。这凸显了对该基因进行严格调控对于正常细胞生理学的必要性。尽管 ATP2B 在许多细胞类型中是重要的 Ca2+ 调节因子，但对其转录调节知之甚少。本研究鉴定了 αAtp2b2 转录本的近端启动子。进一步的研究表明 ATOH1 和 EGR1 调节启动子活性。此外，我们报告 EGR1 增加了两种细胞系中 Atp2b2 转录物的内源表达。电泳迁移率变动分析 (EMSA) 表明 EGR1 与 αAtp2b2 启动子的 CpG 岛中的特定位点结合。这项研究通过以下方式进一步加深了我们对 Atp2b2 调控的理解：(I) 阐明 Atp2b2 的转录调控机制，(II) 识别调节大脑和外周听觉系统中 Atp2b2 表达的转录因子，以及 (III) 为未来调节基因表达的研究提供了可能Atp2b2 的。