NF-κB activation and potentiation of proinflammatory responses by the<i>Helicobacter pylori</i>CagA protein

Brandt, Sabine; Kwok, Terry; Hartig, Roland; König, Wolfgang; Backert, Steffen

doi:10.1073/pnas.0409873102

Cited by 458 publications

(494 citation statements)

References 39 publications

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“…Intracellular CagA undergoes Src-dependent tyrosine phosphorylation and activates a eukaryotic phosphatase, leading to dephosphorylation of host cell proteins and cellular morphological changes (Backert et al, 2000;Higashi et al, 2002;Selbach et al, 2002;Stein et al, 2002). Recently, CagA has been shown to activate ␤-catenin and induce NF-B-mediated interleukin-8 release from gastric epithelial cells (Brandt et al, 2005;Franco et al, 2005). The presence of the cag island also influences the topography of colonization in the stomach, because H. pylori cag Ϫ strains predominate within the mucus gel layer, whereas cag ϩ strains are found immediately adjacent to epithelial cells (Camorlinga-Ponce et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Ogden

Wroblewski

Weydig

et al. 2008

MBoC

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Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons develop cancer. One H. pylori constituent that augments disease risk is the cytotoxin-associated gene (cag) pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Matrix metalloproteinase (MMP)-7, a member of a family of enzymes with tumor-initiating properties, is overexpressed in premalignant and malignant gastric lesions, and H. pylori cag ؉ strains selectively increase MMP-7 protein levels in gastric epithelial cells in vitro and in vivo. We now report that H. pylori-mediated mmp-7 induction is transcriptionally regulated via aberrant activation of p120-catenin (p120), a component of adherens junctions. H. pylori increases mmp-7 mRNA levels in a cagand p120-dependent manner and induces translocation of p120 to the nucleus in vitro and in a novel ex vivo gastric gland culture system. Nuclear translocation of p120 in response to H. pylori relieves Kaiso-mediated transcriptional repression of mmp-7, which is implicated in tumorigenesis. These results indicate that selective and coordinated induction of mmp-7 expression by H. pylori cag ؉ isolates may explain in part the augmentation in gastric cancer risk associated with these strains. INTRODUCTIONHelicobacter pylori induces an inflammatory response in the stomach that persists for decades, and biological costs incurred by this pathogen include an increased risk for gastric adenocarcinoma and non-Hodgkins lymphoma of the stomach (Nomura et al., 1991;Parsonnet et al., 1991;Peterson, 1991;Hansson et al., 1993;Correa, 1996;Uemura et al., 2001;Peek and Blaser, 2002;Moss and Sood, 2003). However, only a fraction of colonized persons ever develop neoplasia, and enhanced cancer risk is related to strain-specific differences, aberrant host responses, and/or specific interactions between microbial and host determinants.H. pylori strains that possess the cytotoxin-associated gene (cag) pathogenicity island increase the risk for cancer compared with strains that lack this genetic locus (Peek and Blaser, 2002). The cag island encodes proteins, such as CagE, that form a type IV secretion system that translocates components of bacterial peptidoglycan and CagA, the product of the terminal gene of the island, into host cells (Asahi et al., 2000;Backert et al., 2000;Odenbreit et al., 2000;Stein et al., 2000;Selbach et al., 2002;Viala et al., 2004). After translocation, peptidoglycan initiates innate immune signaling via activation of the intracellular pattern recognition receptor, Nod-1, and the transcriptional activator nuclear factor-B (NF-B) (Viala et al., 2004). Intracellular CagA undergoes Src-dependent tyrosine phosphorylation and activates a eukaryotic phosphatase, leading to dephosphorylation of host cell proteins and cellular morphological changes (Backert et al., 2000;Higashi et al., 2002;Selbach et al., 2002;Stein et al., 2002). Recently, CagA has been shown to activate ␤-catenin and...

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Section: Introductionmentioning

confidence: 99%

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Ogden

Wroblewski

Weydig

et al. 2008

MBoC

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“…The cagA is reported to be found in more than half of the H. pylori isolates. It is known that cagA is a marker for the cag pathogenicity island and is associated with increased IL-8 production, nuclear factor-kB activation, mucosal inflammation and development of peptic ulcers, atrophic gastritis, and gastric cancer (6). The vacA gene encodes an 87-93 kDa molecular weight VacA protein, which induces cytoplasmic vacuoles in mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Detection of cagA and vacA genotypes of Helicobacter pylori isolates from a university hospital in Ankara region, Turkey

Erdoğdu

Sarıbaş²,

Yilmaz³

2014

Turk J Med Sci

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The cagA and vacA profiles and their association with clinical findings show a distinct geographical distribution. In the present study, we aimed to determine the cagA status and vacA allelic subtypes in strains isolated from a university hospital in Ankara and to evaluate their associations with histopathological and endoscopic findings. Materials and methods:A total of 120 H. pylori strains from stock cultures positive for the ureA gene were randomly included in the present study. Of these strains, cagA and vacA allelic subtypes (s1a, s1b, s2, m1, m2) were examined by polymerase chain reaction.Results: Of the 120 strains, 64 (53.3%) were cagA-positive. However, no significant relationship was found between clinical outcomes and cagA positivity. There were 38 (33.6%) strains that had vacA m1 and 74 (65.5%) that had vacA m2 region. Overall, 75 (70.1%) samples were classified as vacA s1a, 3 (2.8%) as vacA s1b, and 29 (27.1%) as vacA s2. There was no significant relationship between vacA genotypes and endoscopic findings. The predominant vacA genotypes were s1am2 (35.6%) and s1am1 (33.6%), with almost the same rates. Furthermore, cagA positivity was found to be significantly related with the vacA s1am1 genotype. Conclusion:The cagA and vacA profiles of our study population are consistent with the Middle Eastern profile.

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“…On the other hand, CagA also disturbs cell functions in a tyrosine phosphorylation-independent manner, activating a nuclear factor that induces transcription of several inflammatory genes (11). Furthermore, CagA is also capable of activating NF-κβ, which in turn induces interleukin-8 expression (12) and more recently, it has been reported that this bacterial protein deregulate the β-catenin signaling (13).…”

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confidence: 99%

EPIYA motif patterns among Cuban Helicobacter pylori CagA positive strains

Torres¹,

González²,

Melián³

et al. 2011

biomedica

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NF-κB activation and potentiation of proinflammatory responses by theHelicobacter pyloriCagA protein

Cited by 458 publications

References 39 publications

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Detection of cagA and vacA genotypes of Helicobacter pylori isolates from a university hospital in Ankara region, Turkey

EPIYA motif patterns among Cuban Helicobacter pylori CagA positive strains

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