Post-transcriptional regulation of heparanase gene expression by a 3′ AU-rich element
Post-transcriptional regulation of heparanase gene expression by a 3′ AU-rich element
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DOI：
10.1096/fj.10-156372
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发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Vlodavsky, Israel
中科院分区：
文献类型：
--
作者：
Arvatz, Gil;Barash, Uri;Vlodavsky, Israel
乙酰肝素酶上调在越来越多的人类癌症中被记录，与不良预后相关。本研究的目的是确定乙酰肝素酶诱导的机制。我们提供的证据表明，乙酰肝素酶的表达在转录后水平上的调控序列在3'非翻译区（3' UTR）的基因。紧接着乙酰肝素酶cDNA构建3' UTR降低乙酰肝素酶酶活性和蛋白水平，导致细胞侵袭能力降低。我们进一步鉴定了3' UTR内介导乙酰肝素酶下调的185-bp序列，并表征了该区域内富含腺嘌呤（A）/尿嘧啶（U）的共有元件（ARE）。缺失整个185-bp区域或ARE消除了3' UTR的抑制作用，导致乙酰肝素酶水平升高，并形成更大的肿瘤异种移植物，在大小、血管化和Akt激活方面与乙酰肝素酶过表达细胞产生的肿瘤异种移植物难以区分。这些结果表明，ARE的丢失是促进人类癌症中乙酰肝素酶诱导的重要调节机制。Arvatz，G.，巴拉什大学，Nativ，O.，Ilan，N.，弗洛达夫斯基岛3'AU富集元件对乙酰肝素酶基因表达的转录后调控。FASEB J.24，4969-4976（2010）。www.fasebj.org
Heparanase up-regulation was documented in an increasing number of human carcinomas, associated with poor prognosis. The purpose of the current study was to identify mechanisms responsible for heparanase induction. We provide evidence that heparanase expression is regulated at the post-transcriptional level by sequences at the 3' untranslated region (3' UTR) of the gene. Constructing the 3' UTR immediately following the heparanase cDNA reduces heparanase enzymatic activity and protein levels, resulting in decreased cellular invasion capacity. We further identified a 185-bp sequence within the 3' UTR that mediates heparanase down-regulation, and characterized an adenine (A)/uracil (U)-rich consensus element (ARE) within this region. Deletion of the entire 185-bp region or the ARE eliminated the inhibitory effect of the 3' UTR, resulting in elevated heparanase levels and formation of larger tumor xenografts indistinguishable from those produced by heparanase-overexpressing cells in terms of size, vascularization, and Akt activation. These results suggest that loss of the ARE is an important regulatory mechanism contributing to heparanase induction in human cancer.-Arvatz, G., Barash, U., Nativ, O., Ilan, N., Vlodavsky, I. Post-transcriptional regulation of heparanase gene expression by a 3' AU-rich element. FASEB J. 24, 4969-4976 (2010). www.fasebj.org