PMID- 15048882
OWN - NLM
STAT- MEDLINE
DCOM- 20041110
LR  - 20211203
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 91
IP  - 6
DP  - 2004 Apr 15
TI  - TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis.
PG  - 1293-300
AB  - 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.
CI  - Copyright 2004 Wiley-Liss, Inc.
FAU - Radisavljevic, Ziv Manasija
AU  - Radisavljevic ZM
AD  - Harvard University, School of Public Health, Physiology Program, Boston, 
      Massachusetts 02115, USA. zradisav@hsph.harvard.edu
FAU - Gonzalez-Flecha, Beatriz
AU  - Gonzalez-Flecha B
LA  - eng
GR  - CA-09521/CA/NCI NIH HHS/United States
GR  - HL068073/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Androstadienes)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (ran GTP-Binding Protein)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Cells, Cultured
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - Immunosuppressive Agents/pharmacology
MH  - *Mitosis/drug effects
MH  - Mutation/genetics
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Pulmonary Alveoli/cytology/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins/genetics/metabolism
MH  - Signal Transduction/drug effects/genetics
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
MH  - Wortmannin
MH  - ran GTP-Binding Protein/genetics/*metabolism
EDAT- 2004/03/30 05:00
MHDA- 2004/11/13 09:00
CRDT- 2004/03/30 05:00
PHST- 2004/03/30 05:00 [pubmed]
PHST- 2004/11/13 09:00 [medline]
PHST- 2004/03/30 05:00 [entrez]
AID - 10.1002/jcb.20037 [doi]
PST - ppublish
SO  - J Cell Biochem. 2004 Apr 15;91(6):1293-300. doi: 10.1002/jcb.20037.