Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1
Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1
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DOI：
10.1158/0008-5472.can-10-2842
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Taketo, Makoto M.
中科院分区：
文献类型：
--
作者：
Aoki, Koji;Kakizaki, Fumihiko;Taketo, Makoto M.
尾部相关同源异型蛋白CDX 2在肠上皮细胞中表达，在肠上皮细胞中，其对于肠上皮细胞的发育和分化至关重要。有证据表明，CDX 2水平在人结肠癌标本中降低，并且Apc（Delta 716）小鼠中Cdx 2的失活突变显著增加结肠息肉的发病率，这表明了肿瘤抑制功能。在这项研究中，我们研究了CDX 2的转录和非转录功能在抑制结肠肿瘤发生中的作用。CDX 2的突变分析显示，功能丧失通过非转录但同源结构域依赖的机制稳定CDK抑制剂p27（Kip 1），该机制抑制细胞周期蛋白E-CDK 2活性并阻断结肠癌细胞中的G 0/G1-S进展。p27（Kip 1）的稳定性是通过抑制泛素化依赖性蛋白水解介导的，与p27（Kip 1）中Thr 187磷酸化的降低有关。siRNA介导的p27（Kip 1）敲低缓解了CDX 2表达引起的细胞周期蛋白E-CDK 2活性和S期细胞分数的降低。总之，这些结果暗示了CDX 2在由p27（Kip 1）稳定介导的肿瘤抑制中的非转录功能。高达约75%的低CDX 2人结肠癌病变显示p27（Kip 1）水平降低，而约68%的高CDX 2病变保留p27（Kip 1）表达。这些结果表明，低水平的CDX 2通过降低p27（Kip 1）水平加速结肠肿瘤发生。Cancer Res; 71（2）; 593-602. (C)2011年AACR。
Caudal-related homeoprotein CDX2 is expressed in intestinal epithelial cells, in which it is essential for their development and differentiation. A tumor suppressor function is suggested by evidence that CDX2 levels are decreased in human colon cancer specimens and that an inactivating mutation of Cdx2 in Apc(Delta 716) mice markedly increases the incidence of colonic polyps. In this study, we investigated roles for transcriptional and nontranscriptional functions of CDX2 in suppression of colonic tumorigenesis. Mutagenic analysis of CDX2 revealed that loss of function stabilizes CDK inhibitor p27(Kip1) by a nontranscriptional but homeodomain-dependent mechanism that inhibits cyclin E-CDK2 activity and blocks G0/G1-S progression in colon cancer cells. p27(Kip1) stabilization was mediated by an inhibition of ubiquitylation-dependent proteolysis associated with decreased phosphorylation of Thr187 in p27(Kip1). siRNA-mediated knockdown of p27(Kip1) relieved the decrease in cyclin E-CDK2 activity and S-phase cell fraction elicited by CDX2 expression. Together, these results implicate a nontranscriptional function of CDX2 in tumor suppression mediated by p27(Kip1) stabilization. Up to approximately 75% of low-CDX2 human colon cancer lesions show reduced levels of p27(Kip1), whereas approximately 68% of high-CDX2 lesions retain expression of p27(Kip1). These results show that low levels of CDX2 accelerate colon tumorigenesis by reducing p27(Kip1) levels. Cancer Res; 71(2); 593-602. (C) 2011 AACR.