Helicobacter pylori regulates the expression of inhibitors of DNA binding (Id) proteins by gastric epithelial cells.
Id transcription factors control proliferation, differentiation and apoptosis by inhibiting the DNA binding of basic helix-loop-helix transcription factors. Increased expression of Id proteins promotes proliferation, inhibits differentiation, and is associated with intestinal tumorigenesis. We aimed to determine how Helicobacter pylori may alter the expression of Id proteins by gastric epithelial cells: it was hypothesised that H. pylori, a known carcinogen, would result in increased expression of one or more Id family members. In vitro and in vivo models of infection were employed, including treatment of AGS gastric epithelial cells with wild-type H. pylori strains, 60190 and SS1, and Mongolian gerbils infected with H. pylori SS1. A small cohort of human gastric mucosal biopsies was also examined. Treatment of AGS cells with H. pylori resulted in down-regulation of Id1 and Id3. Unexpectedly, expression of the main target of Id proteins, the basic helix-loop-helix transcription factor E2A, was also suppressed, with an associated decrease in E-box binding activity. In contrast, H. pylori induced the expression of the CDK inhibitor p21(WAF-1/cip1), and the homeobox transcription factor, Cdx2, an early marker of intestinal metaplasia of the stomach epithelium. Gastric epithelium from H. pylori-infected gerbils demonstrated similar changes, with decreased Id2, Id3 and E2A, and elevated p21(WAF-1/cip1) expression. In human gastric epithelium also, H. pylori infection was associated with reduced Id and E2A expression. In conclusion, H. pylori alters the expression of Id proteins, in vitro and in vivo; it is hypothesised that these changes contribute to H. pylori-associated pathologies.
Research Centre for Gastroenterology, Institute of Cell and Molecular Sciences, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, 4 Newark Street, London E1 2AT,UK.
Barbara Ada
BA
Manzo
Jean E
JE
Crabtree
M
M
Fiona Campbell
David
D
Tweedle
Christopher S
CS
Potten
Mona
M
Bajaj-Elliott
Ian R
IR
Sanderson
James W
JW
Wilson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004415:Dyspepsia / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology; D005260:Female; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051796:Inhibitor of Differentiation Proteins; D012313:RNA; C407909:TCF3 protein, human