Hypoxic regulation of stability of connective tissue growth factor/CCN2 mRNA by 3′-untranslated region interacting with a cellular protein in human chondrosarcoma cells
Hypoxic regulation of stability of connective tissue growth factor/CCN2 mRNA by 3′-untranslated region interacting with a cellular protein in human chondrosarcoma cells
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DOI：
10.1038/sj.onc.1209129
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发表时间：
2006-02-01
期刊：
影响因子：
8
通讯作者：
Takigawa, M
中科院分区：
文献类型：
--
作者：
Kondo, S;Kubota, S;Takigawa, M
结缔组织生长因子 (CTGF/CCN2) 可由各种形式的应激诱导，例如暴露于高葡萄糖、机械负荷或缺氧。在这里，我们研究了人软骨肉瘤细胞系 HCS-2/8 中缺氧诱导 ctgf/ccn2 的分子机制。缺氧通过改变 3'-非翻译区 (UTR) 介导的 mRNA 稳定性来增加 ctgf/ccn2 mRNA 水平，而不需要从头合成蛋白质。经过一系列广泛的分析，我们最终发现 3'-UTR 内 84 个碱基的顺式抑制元件与细胞质/核蛋白特异性结合。通过进行 UV 交联测定，我们发现细胞质/核蛋白是一个 35 kDa 的分子，以缺氧诱导的方式与顺式元件结合。这些结果表明，ctgf/ccn2 mRNA 3'-UTR 中的顺式元件和反式因子对应物通过确定 ctgf/ccn2 mRNA 的稳定性，在转录后调节中发挥重要作用。
Connective tissue growth factor (CTGF/CCN2) can be induced by various forms of stress such as exposure to high glucose, mechanical load, or hypoxia. Here, we investigated the molecular mechanism involved in the induction of ctgf/ccn2 by hypoxia in a human chondrosarcoma cell line, HCS-2/8. Hypoxia increased the ctgf/ccn2 mRNA level by altering the 3'-untranslated region (UTR)-mediated mRNA stability without requiring de novo protein synthesis. After a series of extensive analyses, we eventually found that the cis-repressive element of 84 bases within the 3'-UTR specifically bound to a cytoplasmic/nuclear protein. By conducting a UV crosslinking assay, we found the cytoplasmic/nuclear protein to be a 35 kDa molecule that bound to the cis-element in a hypoxia-inducible manner. These results suggest that a cis-element in the 3'-UTR of ctgf/ccn2 mRNA and trans-factor counterpart(s) play an important role in the post-transcriptional regulation by determining the stability of ctgf/ccn2 mRNA.