Bai Yun-Qing, Miyake Satoshi, Iwai Takehisa, Yuasa Yasuhito
Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Oncogene. 2003 Sep 11;22(39):7942-9. doi: 10.1038/sj.onc.1206634.
The CDX2 homeobox transcription factor plays key roles in intestinal development and homeostasis. CDX2 is downregulated during colorectal carcinogenesis, whereas overexpression of CDX2 results in growth inhibition and differentiation of colon carcinoma and intestinal cells. However, the means by which CDX2 functions remain poorly understood. p21/WAF1/CIP1 is one of the cyclin-dependent kinase inhibitors. In addition to its role in cell cycle control, p21 plays critical roles in differentiation and tumor suppression. The overlapping in both the expression and function of CDX2 and p21 in the small intestine and colon strongly suggests a link between these two genes. By means of luciferase reporter and electrophoretic mobility shift assays, we show here that CDX2 transactivated and physically interacted with the promoter of p21 in a p53-independent manner. Moreover, overexpression of CDX2 increased the mRNA expression of p21 in HT-29 colon carcinoma cells, as demonstrated by reverse transcription-polymerase chain reaction. These data suggest that p21 is a transcriptional target of CDX2. Our results may thus provide a new mechanism underlying the functions of CDX2.
CDX2同源框转录因子在肠道发育和稳态中发挥关键作用。在结直肠癌发生过程中，CDX2表达下调，而CDX2的过表达则导致结肠癌和肠道细胞的生长抑制与分化。然而，CDX2发挥功能的具体机制仍知之甚少。p21/WAF1/CIP1是细胞周期蛋白依赖性激酶抑制剂之一。除了在细胞周期调控中的作用外，p21在分化和肿瘤抑制中也发挥着关键作用。CDX2与p21在小肠和结肠中的表达及功能存在重叠，这强烈表明这两个基因之间存在联系。通过荧光素酶报告基因实验和电泳迁移率变动分析，我们在此表明，CDX2以不依赖p53的方式反式激活p21启动子并与其发生物理相互作用。此外，如逆转录-聚合酶链反应所示，CDX2的过表达增加了HT-29结肠癌细胞中p21的mRNA表达。这些数据表明p21是CDX2的转录靶点。因此，我们的结果可能为CDX2功能的潜在新机制提供依据。
