Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

Abstract

The p53 protein plays a central role in the prevention of tumorigenesis. Cellular stresses, such as DNA damage and aberrant oncogene activation, trigger induction of p53 that halts cellular proliferation and allows cells to be repaired. If cellular damage is beyond the capability of the repair mechanisms, p53 induces apoptosis or cell cycle arrest, preventing damaged cells from becoming cancerous. However, emerging evidence suggests that the function of p53 needs to be considered as isoform-specific. Here, we report that the expression profile of p53 can be shifted toward inhibitory p53 isoforms by the pathogenic bacterium Helicobacter pylori, which is known for its strong association with gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. We found that interaction of H. pylori with gastric epithelial cells, mediated via the cag pathogenicity island, induces N-terminally truncated ∆133p53 and ∆160p53 isoforms in human cells. Induction of an orthologous p53 isoform, ∆153p53, was also found in H. pylori-infected Mongolian gerbils. The p53 isoforms inhibit p53 and p73 activities, induce NF-κB, and increase survival of infected cells. Expression of ∆133p53, in response to H. pylori infection, is regulated by phosphorylation of c-Jun and activation of activator protein-1–dependent transcription. Together, these results provide unique insights into the regulation of p53 protein and may contribute to the understanding of tumorigenesis associated with H. pylori.

Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

“…This feature would favour the imaging of TERRA transcripts localization at telomeres. AGS cells are telomerase positive cells harbouring a WT p53 gene [30,31]. …”

Modulation of immune responses by the tumor suppressor p53

“…Although H. pylori infection results in p53 degradation [124], the D133p53 and D160p53 isoforms are transcriptionally up-regulated through enhanced alternative P2 promoter activity within the p53 gene in a manner dependent on the H. pylori type IV secretion system (the syringe-like pilus structure whereby bacterial components are transferred Interaction of p53 with the immune response to host cells). The isoforms then enhance NF-kB transcriptional activity, but inhibit WT p53-and p73-proapoptotic and cell cycle arrest effects, which may provide a mechanism of adaptation of H. pylori in host gastric cells [125]. In another example of a p53/ NF-kB positive relationship in the immune response, p53 containing the P72 codon 72 polymorphism, but not the R72 variant, was able to bind to the p65 NF-kB subunit in the mouse thymus and cooperatively induced caspase 4/11 as well as some inflammatory-related genes including Gdf-15 in response to DNA damage [67].…”

Echoes of a Distant Past: The cag Pathogenicity Island of Helicobacter pylori

“…3) (Buti et al 2011). Several articles have also identified abnormal p53 after exposure to H. pylori, including truncated forms that are promoting increased survival of the host cells (Wei et al 2010(Wei et al , 2012. MALT lymphomas can be distinguished from other lymphomas because they occur in various extranodal locations, primarily the stomach, where they are preceded by H. pylori infection (Vicente-Dueñas et al 2012).…”