7159

TP53BP2

53BP2|ASPP2|BBP|P53BP2|PPP1R13A;tumor protein p53 binding protein 2;TP53BP2;tumor protein p53 binding protein 2

BCL2-binding protein|apoptosis-stimulating of p53 protein 2|apoptosis-stimulating protein of p53, 2|renal carcinoma antigen NY-REN-51|tumor protein p53 binding protein, 2|tumor suppressor p53-binding protein 2

1q41

protein-coding

ASPP2 stimulates the apoptotic function of the p53 family in vivo. We show here that ASPP2-/- pups died before weaning. This postnatal lethality was significantly enhanced in p53+/- background and both deletions are synthetic lethal. ASPP2+/- mice developed spontaneous tumors. The tumor onset was accelerated by gamma-irradiation or in p53+/- background. Tumors derived from ASPP2+/- mice retained wild-type ASPP2 allele even though some of them lost p53. These provide the first genetic evidence that ASPP2 is a haploinsufficient tumor suppressor that shares overlapping function(s) with p53 in mouse development and tumor suppression.

Apoptosis Stimulating Protein of p53-2, ASPP2, aka 53BP2L, (encoded by TP53BP2) is a pro-apoptotic member of a family of p53 binding proteins. ASPP2 expression is frequently suppressed in human cancers and numerous studies have consistently demonstrated that ASPP2 inhibits cell growth as well as stimulates apoptosis-at least in part through a p53-mediated pathway. Two independent mouse models have shown that ASPP2 is a haplo-insufficient tumor suppressor and underscore the importance of the role of ASPP2 in human cancer. However, mounting evidence suggests that the mechanism(s) of action for ASPP2 are complex and likely extend beyond stimulation of apoptotic programs. Data highlighting this expanding spectrum of potential ASPP2-mediated pathways is summarized along with new results from recent in vivo models suggesting new avenues for investigation.

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.