Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1.
Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1.
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DOI：
10.1084/jem.20030616
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发表时间：
2003-08-04
期刊：
影响因子：
--
通讯作者：
Prescott SM
中科院分区：
文献类型：
--
作者：
Dixon DA;Balch GC;Kedersha N;Anderson P;Zimmerman GA;Beauchamp RD;Prescott SM
环氧合酶-2（考克斯-2）催化炎症状态下前列腺素形成的限速步骤，而考克斯-2过表达在肿瘤发生中起关键作用。为了解考克斯-2表达的调控机制，我们研究了考克斯-2 mRNA 3′非翻译区（3′UTR）中富含AU的元件（ARE）对COX-2表达的转录后调控作用。RNA结合研究，进行识别ARE结合调节因子，证明了结合的翻译阻遏蛋白TIA-1的考克斯-2 mRNA。TIA-1介导的考克斯-2表达调节的意义在TIA-1无效的成纤维细胞中观察到，其产生比野生型成纤维细胞显著更多的考克斯-2蛋白。然而，TIA-1缺乏并不改变考克斯-2转录或mRNA周转。结肠癌细胞通过增加与考克斯-2 mRNA的多核糖体结合而过度表达考克斯-2，在体外和体内也显示出缺陷的TIA-1结合。这些发现暗示TIA-1作为考克斯-2表达的翻译沉默子起作用，并支持TIA-1的RNA结合失调促进肿瘤中考克斯-2表达的假设。
The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in inflammatory states, and COX-2 overexpression plays a key role in carcinogenesis. To understand the mechanisms regulating COX-2 expression, we examined its posttranscriptional regulation mediated through the AU-rich element (ARE) within the COX-2 mRNA 3′-untranslated region (3′UTR). RNA binding studies, performed to identify ARE-binding regulatory factors, demonstrated binding of the translational repressor protein TIA-1 to COX-2 mRNA. The significance of TIA-1-mediated regulation of COX-2 expression was observed in TIA-1 null fibroblasts that produced significantly more COX-2 protein than wild-type fibroblasts. However, TIA-1 deficiency did not alter COX-2 transcription or mRNA turnover. Colon cancer cells demonstrated to overexpress COX-2 through increased polysome association with COX-2 mRNA also showed defective TIA-1 binding both in vitro and in vivo. These findings implicate that TIA-1 functions as a translational silencer of COX-2 expression and support the hypothesis that dysregulated RNA-binding of TIA-1 promotes COX-2 expression in neoplasia.
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影响因子：
16
作者：
Förch, P;Puig, O;Valcárcel, J
通讯作者：
Valcárcel, J
影响因子：
5.3
作者：
Lasa, M;Mahtani, KR;Clark, AR
通讯作者：
Clark, AR
影响因子：
4.8
作者：
Dixon, DA;Kaplan, CD;Prescott, SM
通讯作者：
Prescott, SM
影响因子：
4.8
作者：
Raghavan, A;Robison, RL;Bohjanen, PR
通讯作者：
Bohjanen, PR
DOI：
10.1083/jcb.147.7.1431
发表时间：
1999-12-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kedersha NL;Gupta M;Li W;Miller I;Anderson P
通讯作者：
Anderson P