No description available.

Infection with the gut-pathogen Helicobacter pylori is the single, most important risk factor in the development of gastric cancer. Although there is a rising incidence in mortality resulting from this malignancy, the exact mechanism underlying the initiation and progression of bacterial-induced gastric tumorigenesis is still not completely understood. Several studies implicate the activation of the Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway as a cellular trigger for promoting carcinogenes. In this thesis, I studied the role of the STAT3 signaling pathway in H. pylori mediated tumorigenesis, and attempted to delineate mechanisms involved. I have found that H. pylori activates the STAT3 signaling pathway both in vitro and in vivo, to promote carcinogenesis. Pivotal for H. pylori mediated STAT3 activation are the bacterial effector protein CagA and host receptor components, the gp130 and the IL-6αR subunits. Further investigation into the mechanism of STAT3 induction identified a key role for cholesterol-enriched membrane lipid rafts. Bacterial invasion and CagA injection into host cells was also dependent on lipid raft integrity. Co-fractionation via the use of sucrose gradients, which permits the isolation of lipid rafts, identified H. pylori CagA to be associated with these membrane microdomains. CagA, once injected into the cell, appears to interact with the inner leaflet of the host plasma membrane via a charge association that either directly or indirectly anchors it to the negatively charged anionic lipids in the cytoplasmic membrane. In addition, janus kinases were recruited to rafts upon H. pylori infection. In this thesis, I present a dynamic model of STAT3 activation, which requires the interaction of lipid raft associated proteins, H. pylori CagA and recruited JAKs with non-lipid raft receptor components to support STAT3 signaling. This study is significant since it provides insight into the possible mechanisms by which H. pylori induces gastric cancer and furthermore, it facilitates the development of novel therapeutic targets directed against bacterial induced carcinogenesis.

OBJETIVO: Presentar un estudio donde se buscará al Helicobacter pylori como factor asociado en la aparición de ulceras pépticas. FINALIDAD: Se busca con el presente estudio contar con una base de datos actual para poder tomar medidas sanitarias en el distrito de Vitarte. MÉTODO: Estudio analítico de tipo caso-control, con una muestra de 264 donde 132 casos y de 132 controles. MATERIALES: Se realiza una revisión de historias clínicas, mediante una ficha se recolecta la información y se procesa en la basas de datos SPSS y EXCEL. RESULTADOS: El Helicobacter pylori tuvo un OR 4.3 (IC 95 % 2,29 -8,11) y una prevalencia de 81%. La prevalencia del sexo femenino fue de 61%. La prevalencia de los casados fue de 42% y la prevalecía de pacientes sin Helicobacter pylori y con una cruz fue de 39%. CONCLUSIONES: El Helicobacter pylori es una factor asociado a la presencia de ulceras pépticas.

Diverse extracellular stimuli, including ultraviolet light, irradiation, heat shock, proinflammatory cytokines, trigger activation of MAPK pathway through phosphorylation on a TGY motif within the kinase activation loop. Protein MAPK appears to play a major role in apoptosis. It has been causally implicated in sepsis and arthritis. The translational small ubiquitin related modifier (SUMO) modification of proteins has been shown to play multiple functional roles in several cellular processes, including signal transduction, protein targeting, stabilization, transcriptional activation and apoptosis. Our previous study demonstrated that the expression levels of SUMO-1 rnRNA and proteins were enhanced in Helicobacter pylori infected human gastric epithelial cells. The activation of MAPK pathway and cellular apoptosis of AGS cell lines were increased during Helicobacter pylori infection. It was hypothesized that Helicobacter pylori functioning as a biological stress that induced MAPK mediated apoptosis which may be regulated by sumoylation. Results showed that MAPK phosphorylation and cellular apoptosis were enhanced in RFP-SUMOs or GFP-MAPK expressing cells, especially during Helicobacter pylori infection. It was inhibited by pretreatment of MAPK inhibitor. The enhanced phosphorylation and apoptosis were observed during GFP-MAPK overexpression. It¡¦s suggested that MAPK is a target protein for SUMOs.

No description available.

Helicobacter pylori (H. pylori) causes peptic ulcer or gastric cancer through different virulence factors including lipopolysaccharides (LPS), the cytotoxin-associated gene A product (CagA), and vacuolating cytotoxin A (VacA) etc. It stimulated mitogen-activated protein (MAP) kinase signaling cascades. Small ubiquitin-related modifier (SUMO) is a member of ubiquitin-related protein modifiers. However, the mechanisms of the involvement of SUMO-1 on H. pylori induced apoptosis were not clear. Our previous study showed that the expression of RFP-SUMO-1 and apoptosis were increased significantly by fluorescence microscopy assays on RFP-SUMO-1 transfectants during H. pylori infection. In addition, the cytoplasmic SUMO-1 was increased during infection and positively associated with apoptosis. Here, how SUMO-1 was involved in the apoptotic signaling enhancement during H. pylori infection was studied. Results showed that H. pylori infection enhanced MAP kinase activation and the effects were stronger on the SUMO-1 overexpressed cells. However, it was not affected by the secretion of CagA or VacA toxins of H. pylori. To investigate the possible role of SUMO-1 on MAPKs mediated signaling pathways, three selective MAPKs inhibitors were used on RFP-SUMO-1 overexpressed cells. Only p38 inhibitor decreased the levels of apoptosis during H. pylori infection and the expression of p53 was increased on RFP-SUMO-1 1 overexpressed cells. Thus, p38 and p53 pathways were suggested to be involved in SUMO-1 enhanced apoptosis during H. pylori infection. In addition, the nuclear localization of NF-£eB and expression of COX-2 were enhanced on RFP-SUMO-1 overexpressed cells. Moreover, more nuclear NF-£eB and cytoplasmic as well as nuclear RFP-SUMO-1 were observed during H. pylori infection. Our data suggest that H. pylori infection enhances SUMO-1 expression which activates MAPKs on both the pro-apoptotic p38-p53 pathway and the anti-apoptotic ERK-NF-£eB-COX2 pathway. The detail mechanisms on how cells making the final decision on the survival or apoptosis were still not clear and deserving to investigate.

Thesis (M. Sc.)--University of Canterbury, 2009. / Typescript (photocopy). Includes bibliographical references (p. 169-189). Also available via the World Wide Web.

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Surgery / Master / Master of Surgery