Mechanism of Egr-1 control of cardiac calcium homeostasis

Egr-1过表达的心脏细胞具有与减少的钙螯合蛋白2（CSQ 2）表达相关的抑制的钙动力学（Kasneci等，App 1）。我们发现Egr-1通过一种新的机制抑制CSQ 2的表达。Egr-1在165 bp区域结合大鼠和小鼠CSQ 2启动子DNA，该区域在两个物种之间具有>75%的同源性，并且包含与CpG岛重叠的Egr-1和SP1共有位点。已知Egr-1与SP 1、p300/CBP和酪蛋白激酶II结合，被PKA、PKC和CKII磷酸化，并被p300/CBP乙酰化。这些修饰或相互作用是否促进激活或抑制取决于所分析的启动子和所使用的组织/细胞类型。我们假设Egr-1取代激活SP1来抑制CSQ 2。由于Egr-1的作用是上下文依赖性的，我们假设Egr-1的修饰和与现有的蛋白质形成的Egr-1复合物：DNA复合物和/或DNA/染色质修饰剂在受抑制的CSQ 2启动子是特定于心脏细胞。

Egr-1 overexpressing cardiac cells have repressed calcium dynamics linked to reduced calsequestrin 2 (CSQ2) expression (Kasneci et al App 1). We found Egr-1 to repress CSQ2 expression by a novel mechanism. Egr-1 binds rat and mouse CSQ2 promoter DNA at a 165 bp region that is >75% homologous between the 2 species and contains Egr-1 and SP1 consensus sites overlapping a CpG island. Egr-1 is known to bind to SP1, p300/CBP and casein kinase II, is phosphorylated by PKA, PKC and CKII and acetylated by p300/CBP. Whether these modifications or interactions promote activation or repression depends upon the promoter analyzed and tissue/cell type used. We hypothesize that Egr-1 displaces activating SP1 to repress CSQ2. Because Egr-1's action is context dependent we hypothesize that the Egr-1 modifications and the Egr-1 complexes formed with existing protein:DNA complexes and/or DNA/chromatin modifiers at the repressed CSQ2 promoter are particular to cardiac cells.