title: Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host.
abstract: Type I strains of Helicobacter pylori (Hp) possess a pathogenicity island, cag, that encodes the effector protein cytotoxin-associated gene A (CagA) and a type four secretion system. After translocation into the host cell, CagA affects cell shape, increases cell motility, abrogates junctional activity, and promotes an epithelial to mesenchymal transition-like phenotype. Transgenic expression of CagA enhances gastrointestinal and intestinal carcinomas as well as myeloid and B-cell lymphomas in mice, but the mechanism of the induced cancer formation is not fully understood. Here, we show that CagA subverts the tumor suppressor function of apoptosis-stimulating protein of p53 (ASPP2). Delivery of CagA inside the host results in its association with ASPP2. After this interaction, ASPP2 recruits its natural target p53 and inhibits its apoptotic function. CagA leads to enhanced degradation of p53 and thereby, down-regulates its activity in an ASPP2-dependent manner. Finally, Hp-infected cells treated with the p53-activating drug Doxorubicin are more resistant to apoptosis than uninfected cells, an effect that requires ASPP2. The interaction between CagA and ASPP2 and the consequent degradation of p53 are examples of a bacterial protein that subverts the p53 tumor suppressor pathway in a manner similar to DNA tumor viruses. This finding may contribute to the understanding of the increased risk of gastric cancer in patients infected with Hp CagA+ strains.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Buti
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Annemarthe G
authors.initials: AG
authors.lastname: Van der Veen
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Antonello
authors.initials: A
authors.lastname: Covacci
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D012306:Risk; D013274:Stomach Neoplasms / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; C080866:cagA protein, Helicobacter pylori; D004317:Doxorubicin; D004247:DNA