Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21.
The Helicobacter pylori CagA bacterial oncoprotein plays a critical role in gastric carcinogenesis. Upon delivery into epithelial cells, CagA causes loss of polarity and activates aberrant Erk signaling. We show that CagA-induced Erk activation results in senescence and mitogenesis in nonpolarized and polarized epithelial cells, respectively. In nonpolarized epithelial cells, Erk activation results in oncogenic stress, up-regulation of the p21(Waf1/Cip1) cyclin-dependent kinase inhibitor, and induction of senescence. In polarized epithelial cells, CagA-driven Erk signals prevent p21(Waf1/Cip1) expression by activating a guanine nucleotide exchange factor-H1-RhoA-RhoA-associated kinase-c-Myc pathway. The microRNAs miR-17 and miR-20a, induced by c-Myc, are needed to suppress p21(Waf1/Cip1) expression. CagA also drives an epithelial-mesenchymal transition in polarized epithelial cells. These findings suggest that CagA exploits a polarity-signaling pathway to induce oncogenesis.
Saito
Yasuhiro
Y
Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Murata-Kamiya
Naoko
N
Hirayama
Toshiya
T
Ohba
Yusuke
Y
Hatakeyama
Masanori
M
D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D016259:Genes, myc; D016481:Helicobacter Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics*; D035683:MicroRNAs; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; C080866:cagA protein, Helicobacter pylori