Mechanisms for Helicobacter pylori CagA-induced cyclin D1 expression that affect cell cycle.
Particular Helicobacter pylori genotypes differentially induce epithelial cell proliferation, but the mechanisms are not characterized. We explored the effect of H. pylori CagA on expression of cyclin D1, an important cell cycle regulator. H. pylori-induced cell survival and cyclin D1 expression were attenuated in a cagA mutant. AP1 and cAMP response element (CRE), but not NF-kappaB, were involved in the induced cyclin D1 expression. Diminished mitogen-activated protein kinase (MAPK) activation, especially involving p38, with downstream effects on AP1 and CRE activation, was observed for the cagA mutant. In total, these data show that cagA+ H. pylori strains are enhanced in their ability to activate MAPKs and downstream transcription factors, increasing cyclin D1 expression, G1-S phase progression, and host cell survival, explaining both the preferential survival of affected host cells, and the enhanced oncogenesis by these bacteria.
Chang
Ya-Jen
YJ
Department of Pharmacology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
Wu
Ming-Shiang
MS
Lin
Jaw-Town
JT
Pestell
Richard G
RG
Blaser
Martin J
MJ
Chen
Ching-Chow
CC
D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016481:Helicobacter Infections / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D016480:Helicobacter pylori / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D005419:Flavonoids; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C080866:cagA protein, Helicobacter pylori; D019938:Cyclin D1; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one