DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor
DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor
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DOI：
10.1158/0008-5472.can-05-2415
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发表时间：
2006-07-01
期刊：
影响因子：
11.2
通讯作者：
Lee, Yan-Hwa Wu
中科院分区：
文献类型：
--
作者：
Chao, Chi-Hong;Chen, Chun-Ming;Lee, Yan-Hwa Wu
DDX 3是一种具有多种生物学功能的DEAD box RNA解旋酶。利用集落形成实验，我们的结果显示，DDX 3抑制各种肿瘤细胞的殖民地形成能力，这种抑制可能是由于DDX 3引起的生长速率降低。此外，我们确定p21（waf 1/cip 1），一个周期蛋白依赖性激酶抑制剂，作为DDX 3的靶基因，和p2.1（waf 1/cip 1）表达的上调占DDX 3的集落抑制活性。P21（waf 1/cip 1）启动子转录起始位点的-123 ~-63区域内的4个Sp1位点是DDX 3对P21（waf 1/cip 1）启动子应答的关键。DDX 3与Sp1相互作用，协同上调p21启动子活性（waf 1/cip 1）。为了确定DDX 3在临床癌症中的相关性，还检查了DDX 3在各种肿瘤中的表达谱。DDX 3 mRNA和蛋白表达在58%~ 73%的肝癌组织中呈下降趋势，P21（waf 1/cip 1）表达下降与p53状态无关。此外，在> 70%的皮肤鳞状细胞癌样品中也观察到从细胞核到细胞质的亚细胞定位的改变。由于DDX 3具有肿瘤抑制功能，如生长抑制特性和p21（waf 1/cip 1）启动子的转录激活，并通过下调基因表达或改变肿瘤细胞中的亚细胞定位而失活，所有这些特征共同表明DDX 3可能是候选的肿瘤抑制因子。
DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21(waf1/cip1), a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p2.1(waf1/cip1) expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on P21(waf1/cip1) Promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the -123 to -63 region, relative to the transcription start site of P21(waf1/cip1) Promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21(waf1/cip1). To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in similar to 58% to 73% of hepatoma specimens, which led to the reduction of P21(waf1/cip1) expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in > 70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21(waf1/cip1) promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor.