Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner

Jinxiong Wei, Jennifer M. Noto, Elena Zaika, Judith Romero-Gallo, Maria Blanca Piazuelo, Barbara Schneider, Wael El-Rifai, Pelayo Correa, Richard M. Peek, Alexander Zaika

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Objective Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori. Design Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins. Results: Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling. Conclusions: Our results provide novel evidence that tumorigenicity associated with H. pylori infection is linked to inhibition of p53 protein by CagA. We propose a model in which CagA-induced degradation of p53 protein is determined by a relative level of p14ARF. In cells in which p14ARF levels were decreased due to hypermethylation or deletion of the p14ARF gene, H. pylori efficiently degraded p53, whereas p53 is protected in cells expressing high levels of p14ARF.

Original languageEnglish (US)
Pages (from-to)1040-1048
Number of pages9
JournalGut
Volume64
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

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Tumor Suppressor Protein p14ARF
Cytotoxins
Helicobacter pylori
Proteolysis
Stomach
Proteins
Virulence Factors
Genes
Neoplastic Cell Transformation
Ubiquitin-Protein Ligases
Gene Deletion
Helicobacter Infections
Immunoblotting
Small Interfering RNA
Stomach Neoplasms
Adenocarcinoma
Epithelium
Immunohistochemistry
Biopsy

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Wei, J., Noto, J. M., Zaika, E., Romero-Gallo, J., Piazuelo, M. B., Schneider, B., ... Zaika, A. (2015). Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut, 64(7), 1040-1048. https://doi.org/10.1136/gutjnl-2014-307295

Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. / Wei, Jinxiong; Noto, Jennifer M.; Zaika, Elena; Romero-Gallo, Judith; Piazuelo, Maria Blanca; Schneider, Barbara; El-Rifai, Wael; Correa, Pelayo; Peek, Richard M.; Zaika, Alexander.

In: Gut, Vol. 64, No. 7, 01.07.2015, p. 1040-1048.

Research output: Contribution to journalArticle

Wei, J, Noto, JM, Zaika, E, Romero-Gallo, J, Piazuelo, MB, Schneider, B, El-Rifai, W, Correa, P, Peek, RM & Zaika, A 2015, 'Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner', Gut, vol. 64, no. 7, pp. 1040-1048. https://doi.org/10.1136/gutjnl-2014-307295
Wei J, Noto JM, Zaika E, Romero-Gallo J, Piazuelo MB, Schneider B et al. Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut. 2015 Jul 1;64(7):1040-1048. https://doi.org/10.1136/gutjnl-2014-307295
Wei, Jinxiong ; Noto, Jennifer M. ; Zaika, Elena ; Romero-Gallo, Judith ; Piazuelo, Maria Blanca ; Schneider, Barbara ; El-Rifai, Wael ; Correa, Pelayo ; Peek, Richard M. ; Zaika, Alexander. / Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. In: Gut. 2015 ; Vol. 64, No. 7. pp. 1040-1048.
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abstract = "Objective Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori. Design Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins. Results: Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling. Conclusions: Our results provide novel evidence that tumorigenicity associated with H. pylori infection is linked to inhibition of p53 protein by CagA. We propose a model in which CagA-induced degradation of p53 protein is determined by a relative level of p14ARF. In cells in which p14ARF levels were decreased due to hypermethylation or deletion of the p14ARF gene, H. pylori efficiently degraded p53, whereas p53 is protected in cells expressing high levels of p14ARF.",
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AU - Noto, Jennifer M.

AU - Zaika, Elena

AU - Romero-Gallo, Judith

AU - Piazuelo, Maria Blanca

AU - Schneider, Barbara

AU - El-Rifai, Wael

AU - Correa, Pelayo

AU - Peek, Richard M.

AU - Zaika, Alexander

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N2 - Objective Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori. Design Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins. Results: Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling. Conclusions: Our results provide novel evidence that tumorigenicity associated with H. pylori infection is linked to inhibition of p53 protein by CagA. We propose a model in which CagA-induced degradation of p53 protein is determined by a relative level of p14ARF. In cells in which p14ARF levels were decreased due to hypermethylation or deletion of the p14ARF gene, H. pylori efficiently degraded p53, whereas p53 is protected in cells expressing high levels of p14ARF.

AB - Objective Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori. Design Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins. Results: Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling. Conclusions: Our results provide novel evidence that tumorigenicity associated with H. pylori infection is linked to inhibition of p53 protein by CagA. We propose a model in which CagA-induced degradation of p53 protein is determined by a relative level of p14ARF. In cells in which p14ARF levels were decreased due to hypermethylation or deletion of the p14ARF gene, H. pylori efficiently degraded p53, whereas p53 is protected in cells expressing high levels of p14ARF.

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