Fig 1.
Outline of the regulation of cellular stresses by p53.
p53 protein is induced by multiple cellular stresses leading to transcriptional up-regulation of p53 target genes that are involved in regulation of apoptosis, proliferation, metabolism, and immune response. Under normal (unstressed) conditions, levels of p53 protein are tightly controlled by HDM2 E3 ubiquitin ligase, which ubiquitinates p53 leading to its proteasomal degradation. The p14ARF tumor suppressor, which functions upstream of HDM2 and p53, is required for accumulation of p53 under oncogenic stress. The role of p14ARF is to inhibit proteasomal degradation of p53 by sequestering the HDM2 protein in the nucleoli and inhibiting its E3 ligase activity.
Fig 2.
Interaction between H. pylori and gastric epithelial cells results in cellular stress.
After adherence, H. pylori translocates CagA protein into host cells using the T4SS. Translocated CagA is rapidly tyrosine phosphorylated by host kinases c-Src and c-Abl and binds to SHP2 phosphatase, leading to alteration of intracellular signaling, including activation of multiple oncogenic pathways and cytoskeletal rearrangement [22]. H. pylori also produces VacA toxin, which binds to the cell surface and forms oligomers. VacA is internalized and forms anion-selective channels in the membranes of endocytic compartments, resulting in cell vacuolation. In addition, H. pylori compromises the integrity of the host genome by inducing oxidative DNA damage and DNA double-strand breaks [27,28]. Insert: An electron microphotograph of H. pylori attached to the surface of AGS human gastric epithelial cells. AGS cells were co-cultured with H. pylori strain 26695, and cag T4SS pili were visualized by scanning electron microscopy (white arrows).
Fig 3.
Model of p53 down-regulation by H. pylori.
Interaction of H. pylori with gastric epithelial cells leads to translocation of bacterial CagA protein into host cells and activation of PKB/Akt and Erk kinases, which phosphorylate HDM2 protein [20,35,38]. The consequent activation of HDM2 and ARF-BP1 E3 protein ligases induces a rapid degradation of p53 protein. Binding of CagA to ASPP2 protein facilitates this process [29]. Degradation of p53 is strongly suppressed in cells expressing functional p14ARF, since ARF inhibits activities of MDM2 and ARF-BP1 proteins [32].
Fig 4.
Outline of the interactions between bacterial pathogens and the p53 pathway.