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Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation

Oncogene volume 29, pages 5643–5650 (2010)Cite this article

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Abstract

Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for the development of gastric adenocarcinoma. The cagA gene product CagA is injected into gastric epithelial cells and disturbs cellular functions by physically interacting with and deregulating a variety of cellular signaling molecules. RUNX3 is a tumor suppressor in many tissues, and it is frequently inactivated in gastric cancer. In this study, we show that H. pylori infection inactivates the gastric tumor suppressor RUNX3 in a CagA-dependent manner. CagA directly associates with RUNX3 through a specific recognition of the PY motif of RUNX3 by a WW domain of CagA. Deletion of the WW domains of CagA or mutation of the PY motif in RUNX3 abolishes the ability of CagA to induce the ubiquitination and degradation of RUNX3, thereby extinguishing its ability to inhibit the transcriptional activation of RUNX3. Our studies identify RUNX3 as a novel cellular target of H. pylori CagA and also reveal a mechanism by which CagA functions as an oncoprotein by blocking the activity of gastric tumor suppressor RUNX3.

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Acknowledgements

We thank Dr Hatakeyama (University of Tokyo, Japan) for providing the expression vector for CagA-HA and CagA-PR-HA. This work is supported in part by ICR provided by UIUC and NIH Grants DK-085158 (to LFC) and DK-58587, CA-77955 and CA-116087 (to RMP). AL is a recipient of the CMB-TG. YHT is an A*STAR-Illinois Partnership fellow.

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Authors and Affiliations

  1. Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Y H Tsang, A Lamb, B Huang & L F Chen

  2. Institute of Molecular and Cell Biology, Proteos, Singapore

    Y H Tsang & Y Ito

  3. Division of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    J Romero-Gallo & R M Peek Jr

  4. Department of Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    K Ito

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  1. Y H Tsang
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  2. A Lamb
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  3. J Romero-Gallo
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  4. B Huang
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  5. K Ito
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  6. R M Peek Jr
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Correspondence to L F Chen.

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Supplementary Information accompanies the paper on the Oncogene website

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Tsang, Y., Lamb, A., Romero-Gallo, J. et al. Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation. Oncogene 29, 5643–5650 (2010). https://doi.org/10.1038/onc.2010.304

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