Mechanism of Egr-1 control of cardiac calcium homeostasis

Egr-1控制心脏钙稳态的机制

• 批准号: 171274-2009
• 负责人: Chalifour, Lorraine
• 金额: $ 2.55万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=476308
• 关键词: Mechanism; Egr; control; cardiac; calcium

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.

过度表达EGR-1的心肌细胞抑制了与钙调蛋白2(CSQ2)表达减少相关的钙动力学(Kasneci等人应用1)。我们发现Egr-1通过一种新的机制抑制CSQ2的表达。EGR-1与大鼠和小鼠CSQ2启动子DNA结合在165bp的区域，这两个物种之间有75%的同源性，并且包含Egr-1和SP1的共同位点重叠CpG岛。已知EGR-1与SP1、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取代了激活SP1来抑制CSQ2。因为Egr-1的S作用是上下文依赖的，我们假设Egr-1的修饰和与现有蛋白质形成的Egr-1复合体：DNA复合体和/或被抑制的CSQ2启动子上的DNA/染色质修饰物是心肌细胞所特有的。