Helicobacter-induced intestinal metaplasia in the stomach correlates with Elk-1 and serum response factor induction of villin.
Chronic Helicobacter pylori infection results in serious sequelae, including atrophy, intestinal metaplasia, and gastric cancer. Intestinal metaplasia in the stomach is defined by the presence of intestine-like cells expressing enterocyte-specific markers, such as villin. In this study, we demonstrate that villin is expressed in intestine-like cells that develop after chronic infection with H. pylori in both human stomach and in a mouse model. Transfection studies were used to identify specific regions of the villin promoter that are inducible by exposure of the cells to H. pylori. We demonstrated that induction of the villin promoter by H. pylori in a human gastric adenocarcinoma cell line (AGS) required activation of the Erk pathway. Elk-1 and the serum response factor (SRF) are downstream transcriptional targets of the Erk pathway. We observed inducible binding of Elk-1 and the SRF after 3 and 24 h of treatment with H. pylori, suggesting that the bacteria alone are sufficient to initiate a cascade of signaling events responsible for villin expression. Thus, H. pylori induction of villin in the stomach correlates with activation and cooperative binding of Elk-1 and the SRF to the proximal promoter of villin.
Rieder
Gabriele
G
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0682, USA.
Tessier
Arthur J
AJ
Qiao
Xiaotan T
XT
Madison
Blair
B
Gumucio
Deborah L
DL
Merchant
Juanita L
JL
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000378:metabolism; D017930:Genes, Reporter; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D008679:Metaplasia / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000096:biosynthesis*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D013270:Stomach / Q000382:microbiology*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C026615:villin; D048051:p38 Mitogen-Activated Protein Kinases