Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21

J Exp Med. 2010 Sep 27;207(10):2157-74. doi: 10.1084/jem.20100602. Epub 2010 Sep 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / biosynthesis
  • Antigens, Bacterial / genetics*
  • Bacterial Proteins / biosynthesis
  • Bacterial Proteins / genetics*
  • Cell Line
  • Cell Polarity / genetics*
  • Cell Transformation, Neoplastic / genetics
  • Cellular Senescence / genetics*
  • Chlorocebus aethiops
  • Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Dogs
  • Epithelial Cells* / metabolism
  • Epithelial Cells* / microbiology
  • Epithelial Cells* / pathology
  • Epithelial-Mesenchymal Transition / genetics
  • Genes, myc
  • Helicobacter Infections / metabolism
  • Helicobacter Infections / microbiology
  • Helicobacter Infections / pathology
  • Helicobacter pylori / genetics*
  • MicroRNAs
  • Signal Transduction / genetics
  • Up-Regulation

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • MicroRNAs
  • cagA protein, Helicobacter pylori