Department of Biological Sciences, Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.
Biochem Biophys Res Commun. 2010 Feb 26;393(1):179-84. doi: 10.1016/j.bbrc.2010.01.118. Epub 2010 Feb 1.
KAI1 is a metastasis suppressor gene known to inhibit cancer metastasis without affecting primary tumorigenicity. Although KAI1 expression has been reported to undergo transcriptional regulation, how its expression is up- or down-regulated by specific upstream signaling pathways has not been studied in detail. In this study, we characterized the regulatory elements within the 500bp upstream region of mouse KAI1 gene and identified a functional hypoxia-response element (HRE) within the promoter region. Hypoxia-dependent induction of KAI1 was directly mediated by hypoxia-inducible factor (HIF)-1alpha binding on the promoter, which subsequently caused increased recruitment of RNA polymerase II for transcriptional activation. The failure of HIF-1alpha recruitment to the KAI1 promoter was observed in Hif-1alpha knockout mouse embryonic fibroblasts. Furthermore, KAI1 protein synthesis was markedly increased in ischemic tissues, suggesting that KAI1 is a hypoxia target gene in vivo.
KAI1 是一种转移抑制基因，已知其能抑制癌症转移而不影响原发性肿瘤形成。尽管已有报道称 KAI1 的表达受到转录调控，但特定的上游信号通路如何上调或下调其表达尚未详细研究。在这项研究中，我们对小鼠 KAI1 基因上游 500bp 区域的调控元件进行了特征分析，并在启动子区域内鉴定到了一个功能性缺氧反应元件（HRE）。缺氧诱导因子（HIF）-1α在启动子上的结合直接介导了 KAI1 的缺氧依赖性诱导，进而导致 RNA 聚合酶 II 的募集增加，从而实现转录激活。在 Hif-1alpha 基因敲除的小鼠胚胎成纤维细胞中观察到 HIF-1α无法募集到 KAI1 启动子。此外，在缺血组织中，KAI1 蛋白的合成显著增加，这表明 KAI1 是体内的一个缺氧靶基因。
