Chronic
            <i>Helicobacter pylori</i>
            Infection Induces an Apoptosis-Resistant Phenotype Associated with Decreased Expression of p27
            <sup>kip1</sup>

Shirin, Haim; Sordillo, Emilia Mia; Kolevska, Tatiana K.; Hibshoosh, Hanina; Kawabata, Yuichi; Oh, Sung Hee; Kuebler, Joachim F.; Delohery, Thomas; Weghorst, Christopher M.; Weinstein, I. Bernard; Moss, Steven F.

doi:10.1128/iai.68.11.6509-6509.2000

Cited by 22 publications

(35 citation statements)

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“…Kip1 levels is predicted to confer an apoptosis-resistant phenotype and increased susceptibility to GC (56). Overall the changes of gene expression pattern induced by H. pylori GroES are in favor of cell proliferation and may therefore contribute to the increased risk for GC observed in humans chronically exposed to H. pylori.…”

Section: Discussionmentioning

confidence: 99%

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Lin

Chang

et al. 2006

Molecular & Cellular Proteomics

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Helicobacter pylori is an important risk factor of gastric cancer (GC). Although many H. pylori virulence factors have been reported, the pathogenic mechanism by which H. pylori infection causes GC remains unclear. The aims of this study were to identify GC-related antigens from H. pylori and characterize their roles in the development of GC. As GC and duodenal ulcer (DU) are considered clinically divergent, we compared two-dimensional immunoblots of an acid-glycine extract of H. pylori probed with serum samples from 15 patients with GC and 15 with DU to find GC-related antigens, which were subsequently identified by mass spectrometry. Many protein spots were recognized by more than one serum, and 24 of these were better recognized by GC sera. The proteins showing higher frequency of recognition in GC group are threonine synthase, rod shape-determining protein, S-adenosylmethionine synthetase, peptide chain release factor 1, DNAdirected RNA polymerase ␣ subunit, co-chaperonin GroES (monomeric and dimeric forms), response regulator OmpR, and membrane fusion protein. Of these proteins, GroES was identified as a dominant GC-related antigen with a much higher seropositivity of GC samples (64.2%, n ‫؍‬ 95) compared with 30.9% for gastritis (n ‫؍‬ 94) and 35.5% for DU (n ‫؍‬ 124). GroES seropositivity was more commonly associated with antral GC than with nonantral GC (odds ratio ‫؍‬ 2.7; 95% confidence interval, 1.1-6.7). In peripheral blood mononuclear cells, GroES stimulated production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor, IL-1␤, tumor necrosis factor-␣, cyclooxygenase-2, and prostaglandin E 2 . Moreover when incubated with gastric epithelial cells, GroES induced expression of IL-8, cell proliferation, and up-regulation of c-jun, c-fos, and cyclin D1 but caused down-regulation of p27 Kip1 . We conclude that GroES of H. pylori is a novel GC-associated virulence factor and may contribute to gastric carcinogenesis via induction of inflammation and promotion of cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Lin

Chang

et al. 2006

Molecular & Cellular Proteomics

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“…H. pylori infection has been associated with increased IL-8 expression and decreased p27 levels (64). Both reduced p27 levels and increased IL-8 levels have been shown to mediate decreased apoptosis (65)(66)(67)(68). When exposed to morevirulent European strains expressing higher levels of cagA, gastric epithelial cells increased IL-8 expression, which promotes the activation and infiltration of inflammatory cells and the reduction of apoptosis.…”

Section: Origin Alters Transcription and Virulence Of H Pylorimentioning

confidence: 99%

Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells

et al. 2013

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g While Helicobacter pylori infects over 50% of the world's population, the mechanisms involved in the development of gastric disease are not fully understood. Bacterial, host, and environmental factors play a role in disease outcome. To investigate the role of bacterial factors in H. pylori pathogenesis, global gene expression of six H. pylori isolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factors cagA, vacA, and babB and were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis. Our data suggest that gene expression profiles of clinical isolates can discriminate strains by phylogeographic origin and that these profiles are associated with changes in expression of the proinflammatory and protumorigenic cytokine IL-8 and levels of apoptosis in host epithelial cells. These findings support the hypothesis that bacterial factors determined by the phylogeographic origin of H. pylori strains may promote increased gastric disease.

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“…23,25 p27 protein is also decreased in H. pylori infection, both in areas of gastritis and in intestinal metaplasia. 26,27 In vitro, the addition of H. pylori to cultured gastric epithelial cells increases proteasome-dependent p27 protein degradation without altering p27 gene transcription. 28 However, it is unknown whether similar mechanisms occur in vivo or whether decreased p27 is restored to normal following H. pylori eradication in chronic gastritis.…”

Section: P27mentioning

confidence: 99%

Altered expression of Skp2, c-Myc and p27 proteins but not mRNA after H. pylori eradication in chronic gastritis

et al. 2006

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Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and non-cardia gastric cancer. Cell cycle progression is dependent on the proteasomal degradation of p27, a cyclin-dependent kinase inhibitor and gastric tumor suppressor, following ubiquitination mediated by Skp2. c-Myc is a transcriptional repressor of p27 and also a target of Skp2. In vitro, H. pylori decreases p27 protein post-translationally. We aimed to determine how p27 is regulated by H. pylori in vivo. The effect of eradicating H. pylori on gastric epithelial p27, Skp2, and c-Myc proteins and mRNA was investigated in 22 patients with chronic gastritis, by immunohistochemistry and laser capture microdissection. The percentage of gastric antral epithelial cells expressing p27 protein was significantly higher after eradication of H. pylori (mean7s.e.m. 3772.4% preeradication vs 5572.8% post-eradication; Po0.001), while Skp2 and c-Myc protein-expressing cells were lower (Skp2: 3573.8 vs 2372.6%, P ¼ 0.009; c-Myc: 4773.6 vs 3073.8%, Po0.001). mRNA expressions of p27, Skp2, and c-Myc (normalized for 18SrRNA) were not changed by H. pylori eradication. H. pylori increases c-Myc and decreases gastric epithelial p27 protein expression in association with increased expression of Skp2, the regulator of p27's ubiquitin ligase complex. H. pylori may influence cell cycle progression and carcinogenesis through post-translational effects on specific gene expression.

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Chronic Helicobacter pylori Infection Induces an Apoptosis-Resistant Phenotype Associated with Decreased Expression of p27 ^kip1

Cited by 22 publications

References 0 publications

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells

Altered expression of Skp2, c-Myc and p27 proteins but not mRNA after H. pylori eradication in chronic gastritis

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Chronic Helicobacter pylori Infection Induces an Apoptosis-Resistant Phenotype Associated with Decreased Expression of p27 kip1

Cited by 22 publications

References 0 publications

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells

Altered expression of Skp2, c-Myc and p27 proteins but not mRNA after H. pylori eradication in chronic gastritis

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Chronic Helicobacter pylori Infection Induces an Apoptosis-Resistant Phenotype Associated with Decreased Expression of p27 ^kip1