Helicobacter pylori bacteria alter the p53 stress response via ERK-HDM2 pathway
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Vikas Bhardwaj1,2, Jennifer M. Noto4, Jinxiong Wei1,2, Claudia Andl2,3, Wael El-Rifai2,3, Richard M. Peek3,4, Alexander I. Zaika1,2,3
1Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
2Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
3Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
4Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
Alexander I. Zaika, e-mail: email@example.com
Keywords: p53, Helicobacter pylori, gastric tumor, HDM2, CagA
Abbreviations: CagA - cytotoxin-associated gene A, MOI - Multiplicity of Infection
Received: August 5, 2014 Accepted: November 26, 2014 Published: January 22, 2015
H. pylori infection is the strongest known risk factor for gastric cancer. Inhibition of host tumor suppressor mechanisms by the bacteria underlies the development of this disease. Among the tumor suppressors affected by H. pylori are p53 and E-cadherin, which inhibition has been shown to increase the risk of gastric cancer. In this report, we investigated the interaction between E-cadherin and p53 in H. pylori-infected cells. We found that downregulation of E-cadherin leads to cellular stress and activation of p53. In the setting of H. pylori infection, this mechanism, however, is disrupted. We found that although co-culture of gastric epithelial cells with H. pylori led to downregulation of E-cadherin and cellular stress, it resulted in inhibition of p53, which is mediated by intracellular Erk kinases and HDM2 protein induced by H. pylori. Experimental inhibition of HDM2/p53 interactions restored p53 activity, and decreased survival of infected cells. Collectively, our results revealed that regulation of p53 and E-cadherin is tightly linked through the p53 stress response mechanism that is inhibited by H. pylori via activation of Erk1/2-HDM2-p53 pathway leading to survival of damaged cells. This might be advantageous to the bacteria but may increase the cancer risk.
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