Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene
Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene
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DOI：
10.1074/jbc.m709776200
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发表时间：
2008-05-16
影响因子：
4.8
通讯作者：
Glembotski, Christopher C.
中科院分区：
文献类型：
--
作者：
Belmont, Peter J.;Tadimalla, Archana;Glembotski, Christopher C.
将细胞暴露于调节生长的条件下会损害内质网（ER）蛋白折叠，导致ER应激和转录因子ATF 6的激活。ATF 6与靶基因中的ER应激反应元件结合，诱导增强ER蛋白折叠能力的蛋白质的表达，这有助于克服应激并促进存活。为了研究ATF 6介导的体内存活机制，我们开发了一种转基因小鼠模型，该模型表达一种新的条件激活形式的ATF 6。我们先前表明，激活ATF 6可以保护ATF 6转基因小鼠的心脏免受ER应激。在本研究中，转录谱鉴定了调节性钙调神经磷酸酶相互作用蛋白-1（MCIP 1），也称为钙调神经磷酸酶1（RCAN 1）的调节因子，作为一种新型的ATF 6诱导基因，编码一种已知的钙调神经磷酸酶/活化T细胞核因子（NFAT）调节因子，在许多组织中介导生长和发育。在培养的心肌细胞中，腺病毒（AdV）介导的过表达激活的ATF 6诱导RCAN 1启动子，上调RCAN 1 mRNA，抑制钙调磷酸酶活性，并发挥显著的生长调节作用，抑制RCAN 1靶向的小干扰RNA。这些结果表明，RCAN 1是一种新的ATF 6靶基因，可能协调生长和ER应激信号通路。通过调节生长，RCAN 1可以减少ER蛋白折叠的需要，从而帮助克服压力并提高存活率。此外，这些结果表明，RCAN 1也可能是生长和ER应激信号在许多其他组织，依赖于钙调磷酸酶/NFAT信号传导的最佳生长和发育的新的集成商。
Exposing cells to conditions that modulate growth can impair endoplasmic reticulum (ER) protein folding, leading to ER stress and activation of the transcription factor, ATF6. ATF6 binds to ER stress response elements in target genes, inducing expression of proteins that enhance the ER protein folding capacity, which helps overcome the stress and foster survival. To examine the mechanism of ATF6-mediated survival in vivo, we developed a transgenic mouse model that expresses a novel conditionally activated form of ATF6. We previously showed that activating ATF6 protected the hearts of ATF6 transgenic mice from ER stresses. In the present study, transcript profiling identified modulatory calcineurin interacting protein-1 (MCIP1), also known as regulator of calcineurin 1 (RCAN1), as a novel ATF6-inducible gene that encodes a known regulator of calcineurin/nuclear factor of activated T cells (NFAT)mediated growth and development in many tissues. The ability of ATF6 to induce RCAN1 in vivo was replicated in cultured cardiac myocytes, where adenoviral (AdV)-mediated overexpression of activated ATF6 induced the RCAN1 promoter, up-regulated RCAN1 mRNA, inhibited calcineurin phosphatase activity, and exerted a striking growth modulating effect that was inhibited by RCAN1-targeted small interfering RNA. These results demonstrate that RCAN1 is a novel ATF6 target gene that may coordinate growth and ER stress signaling pathways. By modulating growth, RCAN1 may reduce the need for ER protein folding, thus helping to overcome the stress and enhance survival. Moreover, these results suggest that RCAN1 may also be a novel integrator of growth and ER stress signaling in many other tissues that depend on calcineurin/NFAT signaling for optimal growth and development.