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

Tsang, Ying Hung; Lamb, Acacia; Romero–Gallo, Judith; Huang, Bo; Ito, Kosei; Peek, Richard M.; Ito, Yoshiaki; Chen, Linfeng

doi:10.1038/onc.2010.304

Cited by 90 publications

(71 citation statements)

References 32 publications

(39 reference statements)

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“…We chose this strategy to provide an affinity handle at the extremity of the constructs, while allowing for proper integration into possible complexes with host proteins with otherwise minimal perturbations. After overnight induction with doxycycline, 35 S methionine/ cysteine-labeled cells were lysed, and biotinylated proteins were recovered by absorption onto streptavidin-conjugated beads. The material was treated with TEV protease to release CagA and any proteins associated with it, which were then analyzed by SDS/ PAGE and autoradiography.…”

Section: Resultsmentioning

confidence: 99%

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Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

Buti

Spooner

Veen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

204

166

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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.

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Section: Resultsmentioning

confidence: 99%

“…S8). Of note, RUNX3 is also sent to the proteasome after CagA interaction, suggesting a link between CagA and the proteasomal machinery of the infected cell (35).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

Buti

Spooner

Veen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

204

166

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“…Knockout of the gene in a mouse model resulted in a higher degree of glandular atrophy and metaplasia as well as a higher rate of mucosal proliferation and shift of the immune response to the Th1 side [54]. A further example of H. pylori-induced modulation of a tumor suppressor gene is CagA-dependent downregulation of RUNX3 mediated by ubiquitination and subsequent degradation [55]. Further interest is in the differential regulation of gastric or intestinal transcription factors.…”

Section: Differential Gene Regulation In Gcmentioning

confidence: 99%

Gastric Cancer: Clinical Aspects, Epidemiology and Molecular Background

et al. 2011

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In 2010, the WHO introduced the seventh edition of the tumor node metastasis (TNM) classification that provides a more detailed classification for both local tumor invasion (T) and lymph node involvement (N) compared with the previous version. The T and N categories of tumors located in the stomach have been further modified with the intention to ensure a better correlation to the prognostic outcome. For the classification of a pN0, the number of lymph nodes has been adjusted to 16.The description of tumors with origin in the esophagus has been simplified and includes tumors of the esophagogastric junction as well as gastric tumors extending to the proximal 5 cm of the stomach. Major changes are further the subclassification of the categories T1 and T4 and the new N categorization now considering the number of lymph nodes involved within tree categories. Furthermore, positive lymph nodes in the region of the celiac trunc are considered as regional in case of esophageal cancers.The validity of the new classification system in its prognostic efficacy was compared to the previous edition. A study conducted in China proved a better prognostic stratification for the new actualized version [1]. Another study from Korea showed similar results for the new TNM system, proving a more detailed prognostic assessment, especially between T2 and T3 and N1 and N2 tumors [2]. The advantage of the new (7th) edition was mainly confirmed for the prognostic value of accurate lymph node assessment [3].Concerning the classification of early gastric cancer (GC) in the new system, a study from Italy confirmed the usefulness of the new classification for metastatic lymph nodes as a prognostic tool in case of early GC. AbstractThe validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid ⁄ nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the int...

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“…More recently, the N terminus of CagA has become the focus of research interest and several binding partners have been uncovered (Runx3, ASPP2, β-integrin, TAK1, and TRAF) (20)(21)(22)(23). Two groups have determined the crystal structure of a large, 800-aa N-terminal portion of CagA (24,25).…”

mentioning

confidence: 99%

“…Recent data has identified two important tumor suppressors as potential binding targets of CagA, thereby raising the possibility that the oncogenic potential of this virulence factor is also due to manipulation of cellular tumor suppressors. One of these targets is RUNX3 (20,27,28). The second is ASPP2 (21).…”

mentioning

confidence: 99%

Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

Nešić

Buti

Lü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The Cytotoxin associated gene A (CagA) protein of Helicobacter pylori is associated with increased virulence and risk of cancer. Recent proteomic studies have demonstrated an association of CagA with the human tumor suppressor Apoptosis-stimulating Protein of p53-2 (ASPP2). We present here a genetic, biochemical, and structural analysis of CagA with ASPP2. Domain delineation of the 120-kDa CagA protein revealed a stable N-terminal subdomain that was used in a yeast two-hybrid screen that identified the proline-rich domain of ASPP2 as a host cellular target. Biochemical experiments confirm this interaction. The cocrystal structure to 2.0-Å resolution of this N-terminal subdomain of CagA with a 7-kDa proline-rich sequence of ASPP2 reveals that this domain of CagA forms a highly specialized three-helix bundle, with large insertions in the loops connecting the helices. These insertions come together to form a deep binding cleft for a highly conserved 20-aa peptide of ASPP2. ASPP2 forms an extended helix in this groove of CagA, burying more than 1,000 Å 2 of surface area. This interaction is disrupted in vitro and in vivo by structure-based, loss-of-contact point mutations of key residues in either CagA or ASPP2. Disruption of CagA and ASPP2 binding alters the function of ASPP2 and leads to the decreased survival of H. pyloriinfected cells.

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

Cited by 90 publications

References 32 publications

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

Gastric Cancer: Clinical Aspects, Epidemiology and Molecular Background

Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

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