Prof. Masanori HATAKEYAMA The University of Tokyo Japan Link to biosketch

Abstract

Chronic infection with Helicobacter pylori cagA-positive strains is causally associated with the development of gastric cancer. Oncogenic potential of the cagA gene-product CagA has been confirmed by the observation that cagA-transgenic mice spontaneously develop malignant neoplasms. The CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system, where it undergoes tyrosine phosphorylation by host kinases. Tyrosine-phosphorylated CagA binds to pro-oncogenic tyrosine phosphatase SHP2 and thereby stimulates the phosphatase activity, which activates Ras-ERK signaling. CagA also binds to the polarity-regulating serine/threonine kinase PAR1b in a tyrosine phosphorylation-independent manner, thereby causing epithelial cell polarity defects. Although such cell-intrinsic CagA activities contribute to the early phases of gastric carcinogenesis, CagA is no longer required for the maintenance of established gastric cancer, indicating that gastric carcinogenesis occurs through a “Hit-and-Run” mechanism of CagA. In this presentation, we show that the CagA-mediated inactivation of the kinase activity of PAR1b dampens cytoplasmic-to-nuclear translocation of the BRCA1 tumor suppressor by inhibiting PAR1b-mediated BRCA1 phosphorylation on S616. Loss of nuclear BRCA1 induces the cellular state termed “BRCAness” that generates/deteriorates DNA double-strand breaks (DSBs) by destabilizing replication forks while disabling homologous recombination (HR). That being said, CagA-induced DSB simultaneously activates the p53-p21^Cip1 axis and thereby inhibits proliferation of cells with DSBs, which subsequently undergo premature cell senescence. Inactivation of p53, occurring mostly through aging-associated TP53 mutation in gastric epithelial cells, allows proliferation of CagA-delivered cells exhibiting BRCAness-associated genomic instability, from which CagA-independent pre-cancerous cells underlying “Hit-and-Run” carcinogenesis may arise.