Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma
Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma
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DOI：
10.1111/j.1440-1827.2007.02140.x
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发表时间：
2007-09-01
影响因子：
2.2
通讯作者：
Yokozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Fuku, Takeichi;Semba, Shuho;Yokozaki, Hiroshi
由DNA双链断裂诱导的Thr 68（pChk 2）处的检查点激酶2（Chk 2）磷酸化是抑制细胞周期在G（2）期进展所必需的。本研究的目的是研究野生型p53诱导的磷酸酶1（Wip 1或PPM 1D），Chk 2的负调控因子的表达，以更好地了解其在人胃癌中的作用。在非肿瘤性胃粘膜中，大多数上皮细胞表现出Wip 1阳性和pChk 2阴性免疫反应性，而在小凹上皮的表面检测到相反的蛋白表达模式。在53例胃癌组织中，74%的胃癌组织中Wip 1呈强阳性表达，且与肿瘤大小（P = 0.0497）和Chk 2去磷酸化（P = 0.0213）密切相关。在MKN-74胃癌细胞中，电离辐射（IR）诱导的Wip 1上调蛋白水平检测，但Chk 2介导的细胞周期调控机制被破坏。此外，蛋白酶抑制剂Z-Leu-Leu-Leu（ZLLL）在IR存在或不存在的情况下有效上调Wip 1水平，表明Wip 1表达可以在转录后调节。了解胃癌中Wip 1介导的信号通路可能为开发新的化疗和放疗提供有用的信息。
Phosphorylation of checkpoint kinase 2 (Chk2) at Thr68 (pChk2) induced by DNA double-strand breaks is required for inhibition of cell cycle progression in the G(2) phase. The purpose of the present paper was to investigate the expression of wild-type p53-induced phosphatase 1 (Wip1 or PPM1D), a negative regulator of Chk2, to better understand its role in human gastric cancer. In non-neoplastic gastric mucosa, most epithelial cells exhibited Wip1-positive and pChk2-negative immunoreactivity, whereas an inverse pattern of protein expression was detected at the surface of the foveolar epithelium. In tumor tissues, 74% of 53 gastric cancers had intense Wip1 immunoreactivity and close correlation with both tumor size (P = 0.0497) and Chk2 dephosphorylation (P = 0.0213). In MKN-74 gastric cancer cells, ionizing radiation (IR)-induced Wip1 upregulation was detected at protein levels, but the Chk2-mediated cell cycle regulatory mechanism was disrupted. In addition, protease inhibitor Z-Leu-Leu-Leu (ZLLL) effectively upregulated Wip1 levels in the presence or absence of IR, suggesting that Wip1 expression can be modulated post-transcriptionally. Understanding the Wip1-mediated signaling pathway in gastric cancer may provide useful information for the development of new chemo- and radiotherapies.