Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis.
Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis.
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DOI：
10.1158/1541-7786.mcr-09-0502
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Gardner LB
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文献类型：
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作者：
Gardner LB
无义介导的RNA衰变（NMD）一直被认为是快速消除突变mRNA的重要组成机制。最近已经认识到，NMD还降解多种非突变的转录物，并且NMD可以通过多种细胞应激来调节。许多抑制NMD的应激，包括细胞缺氧和氨基酸剥夺，在暴露于不利微环境的细胞中经历，并且几种NMD靶向转录物促进细胞适应这些环境应激。由于对微环境的适应在肿瘤发生中至关重要，并且由于NMD靶向许多突变的肿瘤抑制基因转录物，因此NMD的调节可能在癌症中具有特别重要的意义。本文简要概述了转录本的识别和NMD靶向的机制，并回顾了证据表明NMD是一个受调控的过程，可以动态地改变基因表达。虽然NMD研究的重点一直在确定在NMD中发挥作用的蛋白质和确定NMD靶向转录本，但最近的数据涉及NMD调控的潜在功能意义，包括可变剪接mRNA亚型的稳定性，mRNA作为真正NMD靶点的验证，以及NMD在肿瘤发生中的作用。
Nonsense mediated RNA decay (NMD) has long been viewed as an important constitutive mechanism to rapidly eliminate mutated mRNAs. More recently it has been appreciated that NMD also degrades multiple non-mutated transcripts, and that NMD can be regulated by wide variety of cellular stresses. Many of the stresses that inhibit NMD, including cellular hypoxia and amino acid deprivation, are experienced in cells exposed to hostile microenvironments, and several NMD targeted transcripts promote cellular adaptation in response to these environmental stresses. Because adaptation to the microenvironment is crucial in tumorigenesis, and because NMD targets many mutated tumor suppressor gene transcripts, the regulation of NMD may have particularly important implications in cancer. This review briefly outlines the mechanisms by which transcripts are identified and targeted by NMD and reviews the evidence demonstrating NMD is a regulated process which can dynamically alter gene expression. While much of the focus in NMD research has been in identifying the proteins that play a role in NMD and identifying NMD targeted transcripts, recent data regarding the potential functional significance of NMD regulation, including the stabilization of alternatively spliced mRNA isoforms, the validation of mRNAs as bona-fide NMD targets, and NMD's role in tumorigenesis, are explored.