Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Overview on Molecular Toxicological Aspects of Helicobacter pylori Virulence Factor, Cytotoxin-associated Antigen A (CagA)

헬리코박터 파이로리의 병원성 단백질, CagA에 대한 분자 독성학적 측면에서의 고찰

  • 김병주 (경희대학교 의과대학 약리학 교실, MRC 센터) ;
  • 정화진 (경희대학교 의과대학 약리학 교실, MRC 센터) ;
  • 황지나 (경희대학교 의과대학 약리학 교실, MRC 센터) ;
  • 강석하 (경희대학교 의과대학 약리학 교실, MRC 센터) ;
  • 오세진 (경희대학교 의과대학 약리학 교실, MRC 센터) ;
  • 서영록 (경희대학교 의과대학 약리학 교실, MRC 센터)
  • Published : 2004.09.01
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Abstract

Helicobacter pylori (H. pylori) infects more than half of the people in the world as a major microbe to cause most of gastric diseases. Recently, cytotoxin associated-antigen A (CagA) is believed as one of the most important virulence factors of H. pylori. Molecular toxicological pathway of CagA is necessary to investigate for understanding the pathological and toxicological aspects of H. pylori, since this virulence protein harasses intercellular processes of host cells to get profit for the survival of H. pylori. CagA is coded from cag pathogenicity island (cag PAI) and translocated into host cells by Type 4 secretion system (TFSS). Tyrosine phosphorylation of CagA targets Src homology 2-containing phosphotyrosine phosphatase (SHP-2) to form a CagA-SHP-2 complex. This complex depends on the similarity of sequence between EPIYA motif and Src homology 2 domain (SH2 domain) of CagA. The generation of growth factors is an essential role of CagA in protecting and healing gastric mucosa for the survival of H. pylori. On the other hand, the activation of IL-8 by CagA induces neutrophils generating inflammation and free radicals. Indeed, free radicals are well known carcinogen to induce DNA damage. In addition, the transduction of mitogen-activation signal by CagA is one of the interesting features to understand how to cause cancer. The relationship between cancer and inflammation with CagA was mainly discussed in this review.

Keywords

References

  1. Akopyants, N.S., Clifton, S.W., Kersulyte, D., Crabtree, J.E., Youree, B.E., Reece, C.A., Bukanov, N.O., Drazek, E.S., Roe, B.A. and Berg, D.E (1998): Analyses of the cag pathogenicity island of Helicobacter pylori. Mol. Microbiol., 28, 37-53
  2. Asahi, M., Azuma, T., Ito, S., Ito, Y., Suto, H., Nagai, Y., Tsubokawa, M., Tohyama, Y., Maeda, S., Omata, M., Suzuki, T. and Sasakawa, C. (2000): Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J. Exp. Med., 191, 593-602 https://doi.org/10.1084/jem.191.4.593
  3. Audibert, C., Burucoa, C., Janvier, B. and Fauchere, J.L. (2001): Implication of the structure of the Helicobacter pylori cag pathogenicity island in induction of interleukin-8 secretion. Infect. Immun., 69, 1625-1629
  4. Backert, S., Ziska, E., Brinkmann, V., Zimny-Arndt, U., Fauconnier, A., Jungblut, P.R., Naumann, M. and Meyer, T.F.(2000): Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol., 2, 155-164
  5. Censini, S., Lange, C., Xiang, Z., Crabtree, J.E., Ghiara, P., Borodovsky, M., Rappuoli, R. and Covacci, A. (1996): Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA, 93, 14648-14653
  6. Choi, J., Yoon, S.H., Kim, J.E., Rhee, K.H., Youn, H.S. and Chung, M.H. (2002): Gene-specific oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Int. J. Cancer, 99, 485-490 https://doi.org/10.1002/ijc.10366
  7. Churin, Y., AI-Ghoul, L., Kepp, O., Meyer, T.F., Birchmeier, W and Naumann, M. (2003): Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J. Cell Biol., 161, 249-255 https://doi.org/10.1083/jcb.200208039
  8. Churin, Y., Kardalinou, E., Meyer T.F. and Naumann, M. (2001): Pathogenicity island-dependent activation of Rho GTPases Rac1 and Cdc42 of Rho GTPases Rac1 and Cdc42 in Helicobacter pylori infection. Mol. Microbiol., 40, 815-823
  9. Craanen, M.E., Blok, P., Top, B., Boerrigter, L., Dekker, W., Offerhaus, G.J., Tytgat, G.N. and Rodenhuis, S. (1995): Absence of ras gene mutations in early gastric carcinomas. Gut., 37, 758-762
  10. De Luca, A., Baldi, A., Russo, P., Todisco, A., Altucci, L., Giardullo, N., Pasquale, L., Iaquinto, S., D'Onofrio, V., Parodi, M.C., Paggi, M.G. and Iaquinto, G. (2003): Coexpression of Helicobacter pylori's proteins CagA and HspB induces cell proliferation in AGS gastric epithelial cells, independently from the bacterial infection. Cancer Res., 63, 6350-6356
  11. De Souza, D., Fabri, L.J., Nash, A., Hilton, D.J., Nicola, N.A. and Baca, M. (2002): SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry, 41, 9229-9236
  12. De Freitas, D., Urbano, M., Goulao, M.H., Donato, M.M., Baldaia, C., Martins, M.I., Souto, P., Gregorio, C., Figueiredo, P., Gouveia, H. and Romaozinho, J.M. (2004): The effect of Helicobacter pylori infection on apoptosis and cell proliferation in gastric epithelium. Hepatogastroenterology, 51, 876-82
  13. Farinati, F., Cardin, R., Russo, V.M., Busatto, G., Franco, M. and Rugge, M. (2003): Helicobacter pylori CagA status, mucosal oxidative damage and gastritis phenotype: A potential pathway to cancer? Helicobacter, 8, 227-234
  14. Fischer, W., Puis, J., Buhrdorf, R., Gebert, B., Odenbreit, S.and Haas, R. (2003): Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol. Microbiol., 42, 1337-1348
  15. Hatakeyama, M. (2003): Helicobacter pylori CagA--a potential bacterial oncoprotein that functionally mimics the mammalian Gab Family of adaptor proteins. Microbes and Infection, 5, 143-150
  16. Higashi, H., Nakaya, A., Tsutsumi, R., Yokoyama, K., Fujii, Y., Ishikawa, S., Higuchi, M., Takahashi, A., Kurashima, Y., Teishikata, Y., Tanaka, S., Azuma, T. and Hatakeyama, M. (2004): Helicobacter pylori CagA induces Ras- independent morphogenetic response through SHP-2 recruitment and activation. J. BioI. Chem., 279, 17205-17216 https://doi.org/10.1074/jbc.M309964200
  17. Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T., Asaka, M. and Hatakeyama, M. (2002): SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science, 295, 683-686
  18. Ito, Y., Azuma, T., Ito, S., Suto, H., Miyaji, H., Yamazaki, Y., Kato, T., Kohli, Y., Keida, Y. and Kuriyama, M. (2000): Sequence analysis and clinical significance of the iceA gene from Helicobacter pylori strains in Japan. J. Clin. Microbiol., 38, 483-488
  19. Karita, M., Matsumoto, S. and Kamei, T. (2003): The size of cagA based on repeat sequence has the responsibility of the location of Helicobacter pylori in the gastric mucus and the degree of gastric mucosal inflammation. MicrobioI. Immunol., 47, 619-630
  20. Kiltz, U., Pfaffenbach, B., Schmidt, W.E. and Adamek, R.J. (2002): the lack of influence of CagA positive Helicobacter pylori strains on gastro-esophageal reflux disease. Eur. J. Gastroenterol. Hepatol., 14, 974-984
  21. Ko, J.S. and Seo, J.K. (2002): cag pathogenicity island of Helicobacter pylori in Korean children. Helicobacter, 7, 232-236
  22. Maeda, S., Ogura, K., Yoshida, H., Kanai, F., Ikenoue, T., Kato, N., Shiratori, Y. and Omata, M. (1998): Major virulence factors, VacA and CagA, are commonly positive in Helicobacter pylori isolates in Japan. Gut., 42, 338-343
  23. Meyer-ter-Vehn, T., Covacci, A., Kist, M. and Pahl, H.L.(2000): Helicobacter pylori activates mitogen-activated protein kinase cascades and induces expression of the proto-oncogenes c-fos and c-jun. J. BioI. Chem., 275, 16064-16072
  24. Miehlke, S., Kibler, K., Kim, J.G., Figura, N., Small, S.M., Graham, D.Y. and Go, M.F. (1996): Allelic variation in the cagA gene of Helicobacter pylori obtained from Korea compared to the United States. Am. J. Gastroenterol., 91, 1322-1325
  25. Naito, Y. and Yoshikawa, T. (2002): Molecular and cellular mechanisms involved in Helicobacter pylori-induced inflammation and oxidative stress. Free Radic. BioI. Med., 33, 323-336 https://doi.org/10.1016/S0891-5849(02)00868-7
  26. Naumann, M., Wessler, S., Bartsch, C., Wieland, B., Covacci, A, Haas, R. and Meyer, T.F. (1999): Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island. J. BioI. Chem., 274, 31655-31662 https://doi.org/10.1074/jbc.274.44.31655
  27. Nozawa, Y., Nishihara, K., Peek, R.M., Nakano, M., Uji, T., Ajioka, H., Matsuura, N. and Miyake, H. (2002): Identification of a signaling cascade for interleukin-8 production by Helicobacter pylori in human gastric epithelial cells. Biochem. Pharmacol., 64, 21-30
  28. Puis, J., Fischer, W. and Haas, R. (2002): Activation of Helicobacter pylori CagA by tyrosine phosphorylation is essential for dephosphorylation of host cell proteins in gastric epithelial cells. Mol. Microbiol., 43, 961-969
  29. Segal, E.D., Cha, J., Lo, J., Falkow, S. and Tompkins, L.S. (1999): Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc. Natl. Acad. Sci. USA, 96, 14559-14564
  30. Seo, J.H., Lim, J.W., Kim, H. and Kim, K.H. (2004): Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-kappaB and induces chemokine expression in gastric epithelial AGS cells. Lab Invest., 84, 49-62
  31. Stein, M., Bagnoli, F., Halenbeck, R., Rappuoli, R., Fantl, W.J. and Covacci, A. (2002): c-Src/Lyn kinases activate Helicobaeter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol. Microbiol., 43, 971-980
  32. Tsutsumi, R., Higashi, H., Higuchi, M., Okada, M. and Hatakeyama, M. (2003): Attenuation of Helicobacter pylori CagA x SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J. BioI. Chem., 278, 3664-3670 https://doi.org/10.1074/jbc.M208155200
  33. Yamazaki, S., Yamakawa, A., Ito, Y., Ohtani, M., Higashi, H., Hatakeyama, M. and Azuma, T. (2003): The CagA protein of Helieobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J. Infect. Dis., 187, 334-337 https://doi.org/10.1086/367807