Helicobacter pylori activates the cyclin D1 gene through mitogen-activatedprotein kinase pathway in gastric cancer cells

Helicobacter pylori induces cellular proliferation in host cells, but the m echanism remains unclear. Thus, we examined the effect of H. pylori on cycl in D1, an important regulator of the cell cycle, especially in relation to intracellular signaling pathways. In a Northern blot analysis, cyclin D1 tr anscription in gastric cancer (AGS) cells was enhanced by coculture with H. pylori strain TN2 in a time-dependent and multiplicity-of-infection-depend ent manner. An isogenic mutant form of vacA also increased cyclin D1 transc ription, but mutant forms of cagE or the entire cag pathogenicity island di d not enhance cyclin D1 transcription. These effects were confirmed with a luciferase assay of the cyclin D1 promoter (pD1luc). Cyclin D1 promoter act ivation by H. pylori was inhibited by MEK inhibitors (U0126 and PD98059), i ndicating that the mitogen-activated protein kinase pathway may be involved in intracellular signal transduction. In contrast, transfection of a repor ter plasmid having any point mutations of the NF-KB binding sites in the pr omoter (pD1-kappa B1M, pD1-kappa B2M, or pD1-kappa B1/2M) or cotransfection of dominant negative I kappaB alpha did not affect cyclin D1 activation by H. pylori. In conclusion, H. pylori activates cyclin D1 through the mitoge n-activated protein kinase pathway and not through NF-KB activation in AGS cells. This activation of cyclin D1 is partly dependent on the cag pathogen icity island but not on vacA.