Helicobacter pylori activates the cyclin D1 gene through mitogen-activated protein kinase pathway in gastric cancer cells.
Helicobacter pylori induces cellular proliferation in host cells, but the mechanism remains unclear. Thus, we examined the effect of H. pylori on cyclin D1, an important regulator of the cell cycle, especially in relation to intracellular signaling pathways. In a Northern blot analysis, cyclin D1 transcription in gastric cancer (AGS) cells was enhanced by coculture with H. pylori strain TN2 in a time-dependent and multiplicity-of-infection-dependent manner. An isogenic mutant form of vacA also increased cyclin D1 transcription, but mutant forms of cagE or the entire cag pathogenicity island did not enhance cyclin D1 transcription. These effects were confirmed with a luciferase assay of the cyclin D1 promoter (pD1luc). Cyclin D1 promoter activation by H. pylori was inhibited by MEK inhibitors (U0126 and PD98059), indicating that the mitogen-activated protein kinase pathway may be involved in intracellular signal transduction. In contrast, transfection of a reporter plasmid having any point mutations of the NF-kappaB binding sites in the promoter (pD1-kappaB1M, pD1-kappaB2M, or pD1-kappaB1/2M) or cotransfection of dominant negative IkappaBalpha did not affect cyclin D1 activation by H. pylori. In conclusion, H. pylori activates cyclin D1 through the mitogen-activated protein kinase pathway and not through NF-kappaB activation in AGS cells. This activation of cyclin D1 is partly dependent on the cag pathogenicity island but not on vacA.
Hirata
Y
Y
Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. hiratay-int@h.u-tokyo.ac.jp
Maeda
S
S
Mitsuno
Y
Y
Akanuma
M
M
Yamaji
Y
Y
Ogura
K
K
Yoshida
H
H
Shiratori
Y
Y
Omata
M
M
D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D016481:Helicobacter Infections / Q000382:microbiology / Q000503:physiopathology; D016480:Helicobacter pylori / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000382:microbiology / Q000503:physiopathology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014774:Virulence
D016328:NF-kappa B; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases