Effects of Helicobacter pylori CagA protein on the growth and survival of B lymphocytes, the origin of MALT lymphoma

Umehara, Shintaro; Higashi, Hideaki; Ohnishi, Naomi; Asaka, Masahiro; Hatakeyama, Masanori

doi:10.1038/sj.onc.1207028

Cited by 85 publications

(89 citation statements)

References 27 publications

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“…Recently, it has been reported that ectopic expression of CagA in IL-3-dependent B cells inhibits cell proliferation by suppressing JAK-STAT signaling (43). It seems likely that CagA does not enhance antiapoptotic or proliferative responses in lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pyloriActivates NF-κB via the Alternative Pathway in B Lymphocytes

Ohmae

Hirata

Maeda

et al. 2005

The Journal of Immunology

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Helicobacter pylori causes various gastroduodenal diseases including gastric MALT lymphoma, but the mechanism underlying H. pylori-induced carcinogenesis is not known. The alternative pathway for NF-κB activation, which involves the processing of NF-κB2/p100 to p52, has been implicated in lymphocyte survival, attenuated apoptosis, and secondary lymphoid tissue development. In this study, we investigated H. pylori-induced activation of NF-κB through the alternative pathway in B lymphocytes. In immunoblot and EMSA, H. pylori induced NF-κB2/p100 processing to p52 and subsequent nuclear accumulation in IM-9 (human B cell line) cells and human peripheral blood B cells, but not in AGS (human gastric cancer cell line) cells. The activation of the alternative pathway was LPS-dependent but not cag pathogenicity island-dependent. Alternative pathway activation by H. pylori was associated with attenuated apoptosis. The expression levels of B lymphocyte chemoattractant, EBI-1 ligand chemokine, and stromal cell-derived factor-1α mRNAs were up-regulated in cocultured human B cells and in infected human gastric mucosa. In the infected mucosa, NF-κB2/p100 and p52 were detected immunohistochemically in the cytoplasm and nuclear compartments of lymphocytes, but not in epithelial cells. In summary, H. pylori activates the alternative NF-κB pathway in B lymphocytes. The effects on chemokine production and antiapoptosis mediated by H. pylori-induced processing of NF-κB2/p100 to p52 may drive lymphocytes to acquire malignant potential.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pyloriActivates NF-κB via the Alternative Pathway in B Lymphocytes

Ohmae

Hirata

Maeda

et al. 2005

The Journal of Immunology

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“…Expression Vectors-Mammalian expression vectors for HA-tagged wild-type CagA derived from H. pylori NCTC11637 strain (WT CagA) and its mutants, phosphorylation-resistant mutant CagA and CagA ⌬N mutant, have been described previously (26,28 were generated by deleting five amino-acids composing the EPIYA motif from CagA ⌬BCCC, CagA ⌬ACCC, and CagA ⌬ABCC, respectively. CagA ⌬ABCCCϩEPIYA and CagA ⌬ABCCCϩ3EPIYA were prepared from WT CagA by substituting amino acid residues 869 -1086 with one and three copies of the EPIYA sequence, respectively.…”

Section: Methodsmentioning

confidence: 99%

EPIYA Motif Is a Membrane-targeting Signal of Helicobacter pylori Virulence Factor CagA in Mammalian Cells

Higashi

Yokoyama

Fujii

et al. 2005

Journal of Biological Chemistry

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124

121

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Helicobacter pylori contributes to the development of peptic ulcers and atrophic gastritis. Furthermore, H. pylori strains carrying the cagA gene are more virulent than cagA-negative strains and are associated with the development of gastric adenocarcinoma. The cagA gene product, CagA, is translocated into gastric epithelial cells and localizes to the inner surface of the plasma membrane, in which it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. Tyrosine-phosphorylated CagA specifically binds to and activates Src homology 2-containing protein-tyrosine phosphatase-2 (SHP-2) at the membrane, thereby inducing an elongated cell shape termed the hummingbird phenotype. Accordingly, membrane tethering of CagA is an essential prerequisite for the pathogenic activity of CagA. We show here that membrane association of CagA requires the EPIYA-containing region but is independent of EPIYA tyrosine phosphorylation. We further show that specific deletion of the EPIYA motif abolishes the ability of CagA to associate with the membrane. Conversely, reintroduction of an EPIYA sequence into a CagA mutant that lacks the EPIYA-containing region restores membrane association of CagA. Thus, the presence of a single EPIYA motif is necessary for the membrane localization of CagA. Our results indicate that the EPIYA motif has a dual function in membrane association and tyrosine phosphorylation, both of which are critically involved in the activity of CagA to deregulate intracellular signaling, and suggest that the EPIYA motif is a crucial therapeutic target of cagA-positive H. pylori infection.

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“…Deregulation of intracellular signal transducers by the injected CagA is suspected of being involved in the development of gastric pathogenesis, eventually leading to a gastric adenocarcinoma. In human B lymphocytes, overexpression of cagA through transfection induces activation of extracellular signal-regulated kinase (ERK) and their downstream apoptosis regulators, indicating that CagA has effects on the growth and survival of B lymphocytes and may play a role in the development of MALT lymphomas (21,22).…”

Section: Introductionmentioning

confidence: 99%

Translocation of Helicobacter pylori CagA into Human B Lymphocytes, the Origin of Mucosa-Associated Lymphoid Tissue Lymphoma

et al. 2010

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Infection by cagA-positive Helicobacter pylori (H. pylori) is strongly associated with gastric carcinomas and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. H. pylori translocates the bacterial protein CagA into gastric epithelial cells, and the translocated CagA deregulates intracellular signaling pathways and thereby initiates pathogenesis. This in turn raised the possibility that H. pylori is associated with the development of MALT lymphomas during persistent infection by direct interaction with B lymphocytes. In this work, we showed that CagA can be directly translocated into human B lymphoid cells by H. pylori, and the translocated CagA undergoes tyrosine phosphorylation and binds to intracellular SH-2. Meanwhile, the translocated CagA induces activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in human B lymphoid cells, and upregulates the expressions of Bcl-2 and Bcl-X L , which prevents apoptosis. These results provide the first direct evidence for the role of CagA as a bacterium-derived oncoprotein that acts in human B cells, and further implies that CagA is directly delivered into B cells by H. pylori and is associated with the development of MALT lymphomas.

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Effects of Helicobacter pylori CagA protein on the growth and survival of B lymphocytes, the origin of MALT lymphoma

Cited by 85 publications

References 27 publications

Helicobacter pyloriActivates NF-κB via the Alternative Pathway in B Lymphocytes

Helicobacter pyloriActivates NF-κB via the Alternative Pathway in B Lymphocytes

EPIYA Motif Is a Membrane-targeting Signal of Helicobacter pylori Virulence Factor CagA in Mammalian Cells

Translocation of Helicobacter pylori CagA into Human B Lymphocytes, the Origin of Mucosa-Associated Lymphoid Tissue Lymphoma

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