title: TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis.
abstract: Hydrogen peroxide (H2O2) activates signaling cascades essential for cell proliferation via phosphatidylinositol-3-kinase (PI3K) and Akt. Here we show that induction of mitogenic signaling by H2O2 activates sequentially PI3K, Akt, mammalian target of rapamycin (mTOR), and Ran protein. Akt activation is followed by signaling through the mTOR kinase and upregulation of Ran in primary type II pneumocytes, a cell type implicated in the development of lung adenocarcinoma. Pretreatment of the cells with wortmannin, a specific inhibitor of PI3K, or rapamycin, a specific inhibitor of mTOR kinase, prevented H2O2-increased mitosis. H2O2-induced Akt ser-473 phosphorylation and upregulation of Ran protein were prevented by wortmannin but not by rapamycin, indicating that PI3K is upstream of Akt and mTOR is downstream from Akt. Overexpression of myr-Akt or Ran-wt in type II pneumocytes increased Akt ser-473 phosphorylation and mitosis in a catalase-dependent manner, indicating that H2O2 is essential for Akt and Ran signaling. These results indicate that H2O2-induced mitogenic signaling in primary type II pneumocytes is mediated by PI3K, Akt, mTOR-kinase, and Ran protein.
authors.affiliation: Harvard University, School of Public Health, Physiology Program, Boston, Massachusetts 02115, USA. zradisav@hsph.harvard.edu
authors.forename: Ziv Manasija
authors.initials: ZM
authors.lastname: Radisavljevic
authors.forename: Beatriz
authors.initials: B
authors.lastname: González-Flecha
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D000077191:Wortmannin; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000730:Androstadienes; D006861:Hydrogen Peroxide; D007166:Immunosuppressive Agents; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; D020931:ran GTP-Binding Protein; C546842:MTOR protein, human; C546845:mTOR protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat