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首页> 外文期刊>Molecular and Cellular Biology >A Constitutive Decay Element Promotes Tumor Necrosis Factor Alpha mRNA Degradation via an AU-Rich Element-Independent Pathway
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A Constitutive Decay Element Promotes Tumor Necrosis Factor Alpha mRNA Degradation via an AU-Rich Element-Independent Pathway

机译：本构性衰变元素通过AU丰富的元素独立途径促进肿瘤坏死因子αmRNA的降解。

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摘要

Tumor necrosis factor alpha (TNF-α) expression is regulated by transcriptional as well as posttranscriptional mechanisms, the latter including the control of mRNA decay through an AU-rich element (ARE) in the 3′ untranslated region (UTR). Using two mutant cell lines deficient for ARE-mediated mRNA decay, we provide evidence for a second element, the constitutive decay element (CDE), which is also located in the 3′ UTR of TNF-α. In stably transfected RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS), the CDE continues to target a reporter transcript for rapid decay, whereas ARE-mediated decay is blocked. Similarly, the activation of p38 kinase and phosphatidylinositol 3-kinase in NIH 3T3 cells inhibits ARE-mediated but not CDE-mediated mRNA decay. The CDE was mapped to an 80-nucleotide (nt) segment downstream of the ARE, and point mutation analysis identified within the CDE a conserved sequence of 15 nt that is required for decay activity. We propose that the CDE represses TNF-α expression by maintaining the mRNA short-lived, thereby preventing excessive induction of TNF-α after LPS stimulation. Thus, CDE-mediated mRNA decay is likely to be an important mechanism limiting LPS-induced pathologic processes.
机译：肿瘤坏死因子α（TNF-α）的表达受转录和转录后机制调节，后者包括通过3'非翻译区（UTR）中富含AU的元件（ARE）控制mRNA衰减。我们使用两个缺乏ARE介导的mRNA衰变的突变细胞系，为第二个成分，即组成性衰变元件（CDE）提供了证据，它也位于TNF-α的3'UTR中。在用脂多糖（LPS）刺激稳定转染的RAW 264.7巨噬细胞中，CDE继续靶向报告基因转录物以实现快速衰减，而ARE介导的衰减被阻断。同样，NIH 3T3细胞中p38激酶和磷脂酰肌醇3激酶的激活抑制了ARE介导但CDE介导的mRNA衰减。 CDE被映射到ARE下游的80个核苷酸（nt）片段，并且点突变分析在CDE中确定了衰减活性所需的15 nt保守序列。我们提出，CDE通过维持mRNA的短寿命来抑制TNF-α的表达，从而防止LPS刺激后过度诱导TNF-α。因此，CDE介导的mRNA衰减很可能是限制LPS诱导的病理过程的重要机制。

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