Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

Hatakeyama, Masanori

doi:10.1038/onc.2008.353

Cited by 71 publications

(66 citation statements)

References 82 publications

(88 reference statements)

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“…In this context, injected CagA becomes tyrosine phosphorylated by kinases of the Src and Abl families (23,28) and induces drastic cellular elongation accompanied by migration of H. pylori-infected epithelial cells (26). The molecular mechanism by which CagA triggers the observed changes in cell morphology is still not fully understood, but translocated CagA obviously interferes with the functions of eukaryotic signaling proteins, leading to deregulation of focal adhesions and the actin cytoskeleton (2,12,26).…”

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confidence: 99%

Complex Cellular Responses of Helicobacter pylori-Colonized Gastric Adenocarcinoma Cells

et al. 2011

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Helicobacter pylori is an important class I carcinogen that persistently infects the human gastric mucosa to induce gastritis, gastric ulceration, and gastric cancer. H. pylori pathogenesis strongly depends on pathogenic factors, such as VacA (vacuolating cytotoxin A) or a specialized type IV secretion system (T4SS), which injects the oncoprotein CagA (cytotoxin-associated gene A product) into the host cell. Since access to primary gastric epithelial cells is limited, many studies on the complex cellular and molecular mechanisms of H. pylori were performed in immortalized epithelial cells originating from individual human adenocarcinomas. The aim of our study was a comparative analysis of 14 different human gastric epithelial cell lines after colonization with H. pylori. We found remarkable differences in host cell morphology, extent of CagA tyrosine phosphorylation, adhesion to host cells, vacuolization, and interleukin-8 (IL-8) secretion. These data might help in the selection of suitable cell lines to study host cell responses to H. pylori in vitro, and they imply that different host cell factors are involved in the determination of H. pylori pathogenesis. A better understanding of H. pyloridirected cellular responses can provide novel and more balanced insights into the molecular mechanisms of H. pylori-dependent pathogenesis in vivo and may lead to new therapeutic approaches.

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confidence: 99%

Complex Cellular Responses of Helicobacter pylori-Colonized Gastric Adenocarcinoma Cells

et al. 2011

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“…The MARKs promote epithelial polarization through regulation of tubulin dynamics (Hatakeyama, 2008). This is mediated through phosphorylation of microtubule-associated proteins, including tau, and involves alteration in cell contacts and in E-cadherin localization (Drewes et al, 1997;Cohen et al, 2004Cohen et al, , 2007Elbert et al, 2006).…”

Section: Mechanisms Of Polarity Controlmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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“…About three decades of intense research into H. pylori virulence factors, in particular CagA and VacA, have revealed many aspects of the relationships between this bacterium, the gastric mucosal surface, and the pathogenesis of disease (Miehike et al 2001;Cover and Blanke 2005;Kusters et al 2006;Hatakeyama 2008;Sewald et al 2008a, Wen and. CagA, encoded by the cagA gene, is a marker for the presence of the 40-kb-long genomic Pathogenicity Island, PAI (Covacci et al 1993) and contributes to the inflammatory response by initiating a signal transduction cascade, resulting in interleukin-8 production.…”

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confidence: 99%