Transactivation of the epidermal growth factor receptor by cag+ Helicobacter pylori induces upregulation or the early growtn response gene Egr-1 in gastric epithelial cells

Keates, S; Keates, A. C.; Nath, S.; Peek Jr, R. M.; Kelly, C. P.
October 2005
Gut;Oct2005, Vol. 54 Issue 10, p1363
Academic Journal
Background and aims: Helicobacter pylon, in particular cytotoxin associated gene (cag)+ strains, have been shown to enhance gastric epithelial cell proliferation in vivo, an effect that likely contributes to gastric carcinogenesis. Early growth response gene 1 (Egr-1) is a crucial regulator of cell growth, differentiation, and survival, which is known to ploy a role in carcinogenesis and cancer progression. The aims of this study were to: (1) examine whether H pylori could upregulate Egr-1 in gastric epithelial cell lines; (2) determine whether there was a differential response to infection with different strains; (3) examine the role of the cog pathogen icily island in this process; and (4) elucidate the molecular mechanisms leading to Egr- 1 upregulation. Methods and results: We found that infection of AGS cells with cog+ H pylori resulted in a rapid (1- 2 hours) but transient increase in Egr- 1 mRNA and protein levels whereas coculture with cog- isolates did not elicit this response. Furthermore, two independent cagE- isogenic mutants of H pylon also demonstrated impaired ability to upregulate Egr- 1. Upregulation of Egr- 1 protein was inhibited by the extracellular regulated kinase (ERK)1/2 inhibitor PD98059 and overexpression of dominant negative MEK1 downregulated Egr-1 luciferase reporter gene activity. Treatment of AGS cells with the epidermal growth Factor receptor (EGFR) kinase inhibitors PD153035 and AG1478 resulted in a reduction in H pylori mediated Egr-1 upregulation, demonstrating that EGFR transactivation plays a role in this early cellular process. Conclusions: Our findings show that cog+ H pylori cause rapid induction of Egr- 1 in gastric epithelial cells which may contribute to H pylori mediated pathogenesis.


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