title: Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner.
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.
  
  
  METHODS
  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.
authors: Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Jinxiong
authors: J
authors: Wei
authors: Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Jennifer M
authors: JM
authors: Noto
authors: Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Elena
authors: E
authors: Zaika
authors: Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Judith
authors: J
authors: Romero-Gallo
authors: Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Maria Blanca
authors: MB
authors: Piazuelo
authors: Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Barbara
authors: B
authors: Schneider
authors: Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Wael
authors: W
authors: El-Rifai
authors: Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Pelayo
authors: P
authors: Correa
authors: Division of Gastroenterology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Richard M
authors: RM
authors: Peek
authors: Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors: Alexander I
authors: AI
authors: Zaika
mesh_terms: D000942:Antigens, Bacterial / Q000145:classification / Q000502:physiology*; D001426:Bacterial Proteins / Q000145:classification / Q000502:physiology*; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism; D005753:Gastric Mucosa / Q000382:microbiology; D006801:Humans; D007150:Immunohistochemistry; D013274:Stomach Neoplasms / Q000382:microbiology* / Q000503:physiopathology; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C080866:cagA protein, Helicobacter pylori
keywords: Gastric Cancer; Helicobacter Pylori - Pathogenesis