Misquitta Christine M, Chen Tao, Grover Ashok K
Banting and Best Department of Medical Research, 10th floor Donnelly CCBR, University of Toronto, 160 College Street, Toronto, Ont., Canada M5S 3E1.
Cell Calcium. 2006 Oct;40(4):329-46. doi: 10.1016/j.ceca.2006.04.004. Epub 2006 Jun 12.
Specific sequences (cis-acting elements) in the 3'-untranslated region (UTR) of RNA, together with stabilizing and destabilizing proteins (trans-acting factors), determine the mRNA stability, and consequently, the level of expression of several proteins. Such interactions were discovered initially for short-lived mRNAs encoding cytokines and early genes like c-jun and c-myc. However, they may also determine the fate of more stable mRNAs in a tissue and disease-dependent manner. The interactions between the cis-acting elements and the trans-acting factors may also be modulated by Ca(2+) either directly or via a control of the phosphorylation status of the trans-acting factors. We focus initially on the basic concepts in mRNA stability with the trans-acting factors AUF1 (destabilizing) and HuR (stabilizing). Sarco/endoplasmic reticulum Ca(2+) pumps, SERCA2a (cardiac and slow twitch muscles) and SERCA2b (most cells including smooth muscle cells), are pivotal in Ca(2+) mobilization during signal transduction. SERCA2a and SERCA2b proteins are encoded by relatively stable mRNAs that contain cis-acting stability determinants in their 3'-regions. We present several pathways where 3'-UTR mediated mRNA decay is key to Ca(2+) signalling: SERCA2a and beta-adrenergic receptors in heart failure, renin-angiotensin system, and parathyroid hormones. Other examples discussed include cytokines vascular endothelial growth factor, endothelin and endothelial nitric oxide synthase. Roles of Ca(2+) and Ca(2+)-binding proteins in mRNA stability are also discussed. We anticipate that these novel modes of control of protein expression will form an emerging area of research that may explore the central role of Ca(2+) in cell function during development and in disease.
RNA的3'非翻译区（UTR）中的特定序列（顺式作用元件），与稳定和不稳定蛋白（反式作用因子）一起，决定了mRNA的稳定性，进而决定了几种蛋白质的表达水平。这种相互作用最初是在编码细胞因子和早期基因（如c-jun和c-myc）的短寿命mRNA中发现的。然而，它们也可能以组织和疾病依赖的方式决定更稳定mRNA的命运。顺式作用元件和反式作用因子之间的相互作用也可能被Ca(2+)直接调节，或通过控制反式作用因子的磷酸化状态来调节。我们最初关注mRNA稳定性的基本概念，以及反式作用因子AUF1（不稳定）和HuR（稳定）。肌浆网/内质网Ca(2+)泵，即SERCA2a（心肌和慢肌）和SERCA2b（包括平滑肌细胞在内的大多数细胞），在信号转导过程中的Ca(2+)动员中起关键作用。SERCA2a和SERCA2b蛋白由相对稳定的mRNA编码，这些mRNA在其3'区域含有顺式作用稳定性决定因素。我们介绍了几种3'-UTR介导的mRNA衰变是Ca(2+)信号传导关键的途径：心力衰竭中的SERCA2a和β-肾上腺素能受体、肾素-血管紧张素系统和甲状旁腺激素。讨论的其他例子包括细胞因子血管内皮生长因子、内皮素和内皮型一氧化氮合酶。还讨论了Ca(2+)和Ca(2+)结合蛋白在mRNA稳定性中的作用。我们预计，这些蛋白质表达的新型控制模式将形成一个新兴的研究领域，可能会探索Ca(2+)在发育和疾病过程中细胞功能中的核心作用。
