Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / enzymology*
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Adenocarcinoma / radiotherapy
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Adenocarcinoma / secondary
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Cell Cycle / genetics
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Cell Cycle / radiation effects
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Cell Line, Tumor / enzymology
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Cell Line, Tumor / pathology
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Cell Line, Tumor / radiation effects
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Cell Survival / radiation effects
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Checkpoint Kinase 2
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Cysteine Proteinase Inhibitors / pharmacology
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Enzyme Induction / genetics
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Enzyme Induction / radiation effects
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Female
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Gastric Mucosa / metabolism
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Gastric Mucosa / pathology
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Gene Expression Regulation, Neoplastic*
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Humans
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Immunoenzyme Techniques
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Leupeptins / pharmacology
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Male
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Phosphoprotein Phosphatases / biosynthesis*
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / radiation effects
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Protein Phosphatase 1
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Protein Phosphatase 2C
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Protein Processing, Post-Translational / physiology*
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Protein Processing, Post-Translational / radiation effects
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Protein Serine-Threonine Kinases / biosynthesis*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / radiation effects
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Radiation, Ionizing
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Stomach Neoplasms / enzymology*
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Stomach Neoplasms / pathology
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Stomach Neoplasms / radiotherapy
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / radiation effects
Substances
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Cysteine Proteinase Inhibitors
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Leupeptins
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Tumor Suppressor Protein p53
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Checkpoint Kinase 2
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CHEK2 protein, human
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Protein Serine-Threonine Kinases
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PPM1D protein, human
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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Protein Phosphatase 2C
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde