Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma.
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.
Division of Pathology, Department of Pathology and Microbiology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
Takeichi
T
Fuku
Shuho
S
Semba
Hirokazu
H
Yutori
Hiroshi
H
Yokozaki
D000230:Adenocarcinoma / Q000201:enzymology* / Q000532:radiotherapy / Q000556:secondary; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction / Q000235:genetics / Q000528:radiation effects; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects; D054645:Protein Phosphatase 1; D000071636:Protein Phosphatase 2C; D011499:Protein Processing, Post-Translational / Q000502:physiology* / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D000071636:Protein Phosphatase 2C; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde