Activation of p21 CIP1/WAF1 gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α
Activation of p21 CIP1/WAF1 gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α
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DOI：
10.1016/j.yexcr.2004.08.014
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发表时间：
2005-01-01
影响因子：
3.7
通讯作者：
Sawada, N
中科院分区：
文献类型：
--
作者：
Chiba, H;Itoh, T;Sawada, N
F9小鼠胚胎癌细胞系为研究上皮分化和抗增殖过程提供了一个有吸引力的系统。我们最近建立了表达多西环素诱导的肝细胞核因子（HNF）-4 α的F9细胞，并显示HNF-4 α触发紧密连接分子、闭合蛋白、封闭蛋白-6和封闭蛋白-7的基因表达，以及功能性紧密连接和极化上皮形态的形成（Exp. Cell Res. 286，[2003] 288）。由于这些事件与类维生素A诱导的事件非常相似，我们研究了HNF-4 α是否与类维生素A受体一样参与细胞增殖的控制。我们在此表明，HNF-4 α上调p21基因的表达，但不是p15，p16，p18，p19，或p27基因，在p53-独立的方式，并抑制F9细胞的细胞生长。在大鼠肺内皮细胞中观察到类似的结果，其中HNF-4 α的表达被多西环素有条件地诱导。此外，我们证明，通过报告分析，HNF-4 α显着提高p21启动子的转录活性。由于HNF-4 α不仅在肝脏中表达，而且在含有上皮细胞的器官如肾、肠、胰腺和胃中表达，因此它也可能在这些器官中的上皮形态发生和增殖的调节中发挥关键作用。(C)2004 Elsevier Inc，保留所有权利。
The F9 murine embryonal carcinoma cell line provides an attractive system for studying epithelial differentiation and antiproliferative processes. We have recently established F9 cells expressing doxycycline-inducible hepatocyte nuclear factor (HNF)-4alpha and shown that HNF-4alpha triggers the gene expression of tight-junction molecules, occludin, claudin-6, and claudin-7, as well as formation of functional tight junctions and polarized epithelial morphology (Exp. Cell Res. 286, [2003] 288). Since these events were very similar to those induced by retinoids, we investigated whether HNF-4alpha, like retinoid receptors, was involved in the control of cell proliferation. We herein show that HNF-4alpha up-regulates expression of the p21 gene, but not the p15, p16, p18, p19, or p27 gene, in a p53-independent manner, and inhibits cell growth in F9 cells. Similar results were observed in rat lung endothelial cells, in which expression of HNF-4alpha is conditionally induced by doxycycline. Furthermore, we demonstrate, by reporter assay, that HNF-4alpha significantly elevates the transcriptional activity of the p21 promoter. Since, HNF-4alpha is expressed not only in the liver but also in organs containing epithelial cells, such as kidney, intestine, pancreas, and stomach, it might also play critical roles in the regulation of epithelial morphogenesis and proliferation in these organs. (C) 2004 Elsevier Inc, All rights reserved.