{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:41:25Z","timestamp":1791297685148,"version":"4.1.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"27","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,7,5]]},"abstract":"<jats:p>\n                    Chronic infection with\n                    <jats:italic>cagA<\/jats:italic>\n                    -positive\n                    <jats:italic>Helicobacter pylori<\/jats:italic>\n                    is associated with the development of atrophic gastritis, peptic ulcers, and gastric adenocarcinoma. The\n                    <jats:italic>cagA<\/jats:italic>\n                    gene product CagA is injected into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Translocated CagA disturbs cellular functions by physically interacting with and deregulating intracellular signaling transducers through both tyrosine phosphorylation-dependent and -independent mechanisms. To gain further insights into the pathophysiological activities of CagA in gastric epithelial cells, we executed a genome-wide screening of CagA-responsive genes by using DNA microarray and identified nuclear factor of activated T cells (NFAT) transcription factors whose binding sites were overrepresented in the promoter regions of CagA-activated genes. Results of reporter assays confirmed that CagA was capable of activating NFAT in a manner independent of CagA phosphorylation. Expression of CagA in gastric epithelial cells provoked translocation of NFATc3, a member of the NFAT family, from the cytoplasm to the nucleus and activated an NFAT-regulated gene,\n                    <jats:italic>\n                      p21\n                      <jats:sup>WAF1\/Cip1<\/jats:sup>\n                    <\/jats:italic>\n                    . CagA-mediated NFAT activation was abolished by inhibiting calcineurin or phospholipase C\u03b3 activity. Furthermore, treatment of cells with\n                    <jats:italic>H. pylori<\/jats:italic>\n                    VacA (vacuolating toxin), which inhibits NFAT activity in T lymphocytes, counteracted the ability of CagA to activate NFAT in gastric epithelial cells. These findings indicate that the two major\n                    <jats:italic>H. pylori<\/jats:italic>\n                    virulence factors inversely control NFAT activity. Considering the pleiotropic roles of NFAT in cell growth and differentiation, deregulation of NFAT, either positively or negatively, depending on the relative exposure of cells to CagA and VacA, may contribute to the various disease outcomes caused by\n                    <jats:italic>H. pylori<\/jats:italic>\n                    infection.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0502529102","type":"journal-article","created":{"date-parts":[[2005,6,24]],"date-time":"2005-06-24T20:34:03Z","timestamp":1119645243000},"page":"9661-9666","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":124,"title":["Functional antagonism between\n                    <i>Helicobacter pylori<\/i>\n                    CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells"],"prefix":"10.1073","volume":"102","author":[{"given":"Kazuyuki","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Higashi","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Fujii","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Kondo","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kato","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Azuma","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Wada","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiya","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Aburatani","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; International Center for Medical Research, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan; 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