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Increased wild‐type p53‐induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma
Author(s) -
Fuku Takeichi,
Semba Shuho,
Yutori Hirokazu,
Yokozaki Hiroshi
Publication year - 2007
Publication title -
pathology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.73
H-Index - 74
eISSN - 1440-1827
pISSN - 1320-5463
DOI - 10.1111/j.1440-1827.2007.02140.x
Subject(s) - downregulation and upregulation , foveolar cell , cancer research , dephosphorylation , cancer , phosphatase , biology , kinase , checkpoint kinase 2 , cell cycle , chemistry , gastric mucosa , microbiology and biotechnology , cell cycle checkpoint , phosphorylation , stomach , biochemistry , gene , genetics
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.