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Helicobacter pylori γ-glutamyltranspeptidase induces cell cycle arrest at the G1-S phase transition

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Abstract

In our previous study, we showed that Helicobacter pylori γ-glutamyltranspeptidase (GGT) is associated with H. pylori-induced apoptosis through a mitochondrial pathway. To better understand the role of GGT in apoptosis, we examined the effect of GGT on cell cycle regulation in AGS cells. To determine the effect of recombinant GGT (rGGT) on cell cycle distribution and apoptosis, rGGT-treated and untreated AGS cells were analyzed in parallel by flow cytometry using propidium iodide (PI). We found that rGGT inhibited the growth of AGS cells in a time-dependent manner, and that the pre-exposure of cells to a caspase-3 inhibitor (z-DEVD-fmk) effectively blocked GGT-induced apoptosis. Cell cycle analysis showed G1 phase arrest and apoptosis in AGS cells following rGGT treatment. The rGGT-mediated G1 phase arrest was found to be associated with down-regulation of cyclin E, cyclin A, Cdk 4, and Cdk 6, and the up-regulation of the cyclindependent kinase (Cdk) inhibitors p27 and p21. Our results suggest that H. pylori GGT induces cell cycle arrest at the G1-S phase transition.

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References

  • Ahmed, A., D. Smoot, G. Littleton, R. Tackey, C.S. Walters, F. Kashanchi, C.R. Allen, and H. Ashktorab. 2000. Helicobacter pylori inhibits gastric cell cycle progression. Microbes Infect. 2, 159–169.

    Article  Google Scholar 

  • Baik, S.C., H.S. Yoon, M.H. Chung, W.K. Lee, M.J. Cho, G.H. Ko, C.K. Park, H. Kasai, and K.H. Rhee. 1996. Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res. 56, 1279–1282.

    CAS  PubMed  Google Scholar 

  • Banatvala, N.K., K. Mayo, F. Megraud, R. Jennings, J.J. Deeks, and R.A. Feldman. 1993. The cohort effect and Helicobacter pylori. J. Infect. Dis. 168, 219–221.

    CAS  PubMed  Google Scholar 

  • Busiello, I., R. Acquaviva, A.D. Popolo, T.G. Blanchard, V. Ricci, M. Romano, and R. Zarrilli. 2004. Helicobacter pylori γ-glutamyltranspeptidase upregulates COX-2 and EGF-related peptide expression in human gastric cells. Cell Microbiol. 64, 396–406.

    Google Scholar 

  • Chiou, C.C., C.C. Chan, Y.P. Kuo, and E.C. Chan. 2003. Helicobacter pylori inhibits activity of cdc2 kinase and delays G2/M to G1 progression in gastric adenocarcinoma cell line. Scand. J. Gastroenterol. 38, 147–152.

    Article  CAS  PubMed  Google Scholar 

  • Correa, P. and M.J. Miller. 1998. Carcinogenesis, apoptosis and cell proliferation. Br. Med. Bull. 54, 151–162.

    CAS  PubMed  Google Scholar 

  • Cortes, B.X., O.E. Chaves, T. Lagergard, and M. Thelestam. 1999. The cytolethal distending toxin from the chancroid bacterium Haemophilus ducreyi induces cell-cycle arrest in the G2 phase. J. Clin. Invest. 103, 107–115.

    Article  Google Scholar 

  • Ding, S.Z., M.F. Smith, and J.B. Goldberg. 2008. Helicobacter pylori and mitogen-activated protein kinases regulate the cell cycle, proliferation and apoptosis in gastric epithelial cells. J. Gastroenterol. Hepatol. 23, 67–78.

    Article  Google Scholar 

  • Draetta, G. 1990. Cell cycle control in eukaryote: molecular mechanisms of cdc2 activation. Trends Biochem. Sci. 15, 378–383.

    Article  CAS  PubMed  Google Scholar 

  • Dulic, V., E. Less, and S.I. Reeds. 1992. Association of human cyclin E with a periodic G1-S phase protein kinase. Science (Washington) 257, 1958–1961.

    Article  CAS  Google Scholar 

  • Elledges, S.J. and J.W. Harper. 1994. Cdk inhibitor: on the threshold of checkpoints and development. Curr. Opin. Cell Biol. 6, 847–852.

    Article  Google Scholar 

  • Fan, X., D. Keller, X. Fan, H. Xia, and P. Keeling. 1995. Helicobacter pylori increases proliferation of gastric epithelial cells. Gut 38, 19–22.

    Article  Google Scholar 

  • Grana, X. and E.P. Reddy. 1995. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 11, 211–219.

    CAS  PubMed  Google Scholar 

  • Hall, M. and G. Peters. 1996. Genetic alterations of cyclins, cyclindependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. 68, 67–108.

    Article  CAS  PubMed  Google Scholar 

  • Kim, K.M., S.G. Lee, J.S. Joo, Y.C. Kwon, D.W. Bea, J.Y. Song, H.L Kang, and et al. 2008. Proteomic analysis of Helicobacter pylori J99 outer membrane protein by tandem mass spectrometry. J. Bacteriol. Virol. 38, 1–8.

    Article  CAS  Google Scholar 

  • Kim, K.M., S.G. Lee, M.G. Park, H.L. Kang, W.K. Lee, M.J. Cho, K.H. Rhee, H.S. Youn, and S.C. Baik. 2007. γ-Glutamyltranspeptidase of Helicobacter pylori induces mitochondria-mediated apoptosis in AGS cells. Biochem. Biophys. Res. Commun. 355, 562–567.

    Article  CAS  PubMed  Google Scholar 

  • Lew, D.J., V. Dulic, and S.I. Reed. 1991. Isolation of three novel human cyclins by rescue of G1 cyclin (Cin) function in yeast. Cell 66, 1197–1206.

    Article  CAS  PubMed  Google Scholar 

  • Lowry, O.H., N.J. Rosebrough, A.L. Farr, and R.J. Randal. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275.

    CAS  PubMed  Google Scholar 

  • MacLachlan, T.K., N. Sang, and A. Giordano. 1995. Cyclins, cyclindependent kinases and cdk inhibitors: implications in cell cycle control and cancer. Crit. Rev. Eukaryot. Gene Expr. 5, 127–156.

    CAS  PubMed  Google Scholar 

  • Moss, S.F. 1998. Helicobacter pylori and apoptosis. Yale J. Biol. Med. 71, 53–61.

    CAS  PubMed  Google Scholar 

  • Morgan, D.O. 1995. Principles of CDK regulation. Nature (London) 374, 131–134.

    Article  CAS  Google Scholar 

  • Ohtsubo, M., A.M. Theodoras, J. Schumacher, J.M. Roberts, and M. Pagano. 1995. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol. Cell Biol. 15, 2612–2624.

    CAS  PubMed  Google Scholar 

  • Parker, S.B., G. Eichele, P. Zhang, A. Rawls, A.T. Sands, A. Bradley, E.N. Olson, J.W. Harper, and S.J. Elledge. 1995. P53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science (Washington) 267, 1024–1027.

    Article  CAS  Google Scholar 

  • Peek, R.J., M.J. Blaser, D.J. Mays, M.H. Forsyth, T.L. Cover, S.Y. Song, U. Krishna, and J.A. Pietenpol. 1999. Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle. Cancer Res. 59, 6124–6131.

    CAS  PubMed  Google Scholar 

  • Peres, S.Y., O. Marches, F. Daigle, J.P. Nougayrede, F. Herault, C. Tasca, J. De Rycke, and E. Oswald. 1997. A new cytolethal distending toxin (CDT) from Escherichia coli producing CNF2 blocks HeLa cell division in G2/M phase. Mol. Microbiol. 24, 1095–1107.

    Article  CAS  PubMed  Google Scholar 

  • Rhee, K.H., H.S. Yoon, S.C. Baik, W.K. Lee, M.J. Cho, H.J. Choi, K.Y. Maeng, and K.W. Ko. 1990. Prevalence of Helicobacter pylori Infection in Korea. J. Korean Soc. Microbiol. 6, 475–490.

    Google Scholar 

  • Romano, M., V. Ricci, and R. Zarrilli. 2006. Mechanisms of disease: Helicobacter pylori-related gastric carcinogenesis-implications for chemoprevention. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 622–632.

    Article  CAS  PubMed  Google Scholar 

  • Sandal, T. 2002. Molecular aspects of the mammalian cell cycle and cancer. Oncologist 7, 73–81.

    Article  CAS  PubMed  Google Scholar 

  • Sherr, C.J. 1994. G1 phase progression: cycling on cue. Cell 79, 551–555.

    Article  CAS  PubMed  Google Scholar 

  • Shibayama, K., Y. Doi, N. Shibata, T. Yagi, T. Nada, Y. Iinuma, and Y. Arakawa. 2001. Apoptotic signaling pathway activated by Helicobacter pylori infection and increase of apoptosis-inducing activity under serum-starved conditions. Infect. Immun. 69, 3181–3189.

    Article  CAS  PubMed  Google Scholar 

  • Shibayama, K., J. Wachino, Y. Arakawa, M. Saidijam, N.G. Rutherford, and P.J. Henderson. 2007. Metabolism of glutamine and glutathione via γ-glutamyltranspeptidase and glutamate transport in Helicobacter pylori: possible significance in the pathophysiology of the organism. Mol. Microbiol. 64, 396–406.

    Article  CAS  PubMed  Google Scholar 

  • Shirin, H., E.M. Sordillo, S.H. Oh, H. Yamamoto, T. Delohery, I.B. Weinstein, and S.F. Moss. 1999. Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial cells. Cancer Res. 15, 2277–2281.

    Google Scholar 

  • Swanton, C. 2004. Cell-cycle targeted therapies. Lancet Oncol. 5, 27–36.

    Article  CAS  PubMed  Google Scholar 

  • Vermeulen, K., D.R. Van Bockstaele, and Z.N. Berneman. 2003. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 36, 131–149.

    Article  CAS  PubMed  Google Scholar 

  • Wagner, S., W. Beil, J. Westermann, R. Logan, C. Bock, C. Trautwein, J. Belck, and M. Manns. 1997. Regulation of gastric epithelial cell growth by H. pylori: Evidence for a major role of apoptosis. Gastroenterology 113, 1836–1847.

    Article  CAS  PubMed  Google Scholar 

  • Whitehouse, C.A., P.B. Balbo, E.C. Pesci, D.L. Cottle, P.M. Mirabito, and C.L. Pickett. 1998. Campylobacter jejuni cytolethal distending toxin causes a G2-phase cell cycle block. Infect. Immun. 66, 1934–1940.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology, Gyeongsang National University School of Medicine, Jinju, 660-751, Republic of Korea

    Kyung-Mi Kim, Jung-Min Kim, Do-Su Kim, Jea-Young Song, Hyung-Lyun Kang, Woo-Kon Lee, Myung-Je Cho, Kwang-Ho Rhee & Seung-Chul Baik

  2. Department of Pediatrics, Gyeongsang National University School of Medicine, Jinju, 660-751, Republic of Korea

    Hee-Shang Youn

  3. Research Institute of Life Science, Gyeongsang National University School of Medicine, Jinju, 660-751, Republic of Korea

    Hyung-Lyun Kang, Woo-Kon Lee, Myung-Je Cho, Kwang-Ho Rhee & Seung-Chul Baik

  4. National Institute of Animal Science, RDA, Suwon, 441-706, Republic of Korea

    Seung-Gyu Lee

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  1. Kyung-Mi Kim
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Correspondence to Seung-Chul Baik.

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Kim, KM., Lee, SG., Kim, JM. et al. Helicobacter pylori γ-glutamyltranspeptidase induces cell cycle arrest at the G1-S phase transition. J Microbiol. 48, 372–377 (2010). https://doi.org/10.1007/s12275-010-9293-8

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