PMID- 8895571
OWN - NLM
STAT- MEDLINE
DCOM- 19961216
LR  - 20211203
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 15
IP  - 19
DP  - 1996 Oct 1
TI  - Direct inhibition of the signaling functions of the mammalian target of rapamycin 
      by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002.
PG  - 5256-67
AB  - The immunosuppressant, rapamycin, inhibits cell growth by interfering with the 
      function of a novel kinase, termed mammalian target of rapamycin (mTOR). The 
      putative catalytic domain of mTOR is similar to those of mammalian and yeast 
      phosphatidylinositol (PI) 3-kinases. This study demonstrates that mTOR is a 
      component of a cytokine-triggered protein kinase cascade leading to the 
      phosphorylation of the eukaryotic initiation factor-4E (eIF-4E) binding protein, 
      PHAS-1, in activated T lymphocytes. This event promotes G1 phase progression by 
      stimulating eIF-4E-dependent translation initiation. A mutant YAC-1 T lymphoma 
      cell line, which was selected for resistance to the growth-inhibitory action of 
      rapamycin, was correspondingly resistant to the suppressive effect of this drug 
      on PHAS-1 phosphorylation. In contrast, the PI 3-kinase inhibitor, wortmannin, 
      reduced the phosphorylation of PHAS-1 in both rapamycin-sensitive and -resistant 
      T cells. At similar drug concentrations (0.1-1 microM), wortmannin irreversibly 
      inhibited the serine-specific autokinase activity of mTOR. The autokinase 
      activity of mTOR was also sensitive to the structurally distinct PI 3-kinase 
      inhibitor, LY294002, at concentrations (1-30 microM) nearly identical to those 
      required for inhibition of the lipid kinase activity of the mammalian p85-p110 
      heterodimer. These studies indicate that the signaling functions of mTOR, and 
      potentially those of other high molecular weight PI 3-kinase homologs, are 
      directly affected by cellular treatment with wortmannin or LY294002.
FAU - Brunn, G J
AU  - Brunn GJ
AD  - Department of Pharmacology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Williams, J
AU  - Williams J
FAU - Sabers, C
AU  - Sabers C
FAU - Wiederrecht, G
AU  - Wiederrecht G
FAU - Lawrence, J C Jr
AU  - Lawrence JC Jr
FAU - Abraham, R T
AU  - Abraham RT
LA  - eng
GR  - AR41180/AR/NIAMS NIH HHS/United States
GR  - CA52995/CA/NCI NIH HHS/United States
GR  - DK28312/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Androstadienes)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromones)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-2)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoproteins)
RN  - 0 (Polyenes)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 35094-46-3 (adenosine 5'-O-(3-thiotriphosphate))
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - T8ID5YZU6Y (Dithiothreitol)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Adenosine Triphosphate/analogs & derivatives/pharmacology
MH  - Androstadienes/*pharmacology
MH  - Animals
MH  - Brain Chemistry
MH  - *Carrier Proteins
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Chromones/*pharmacology
MH  - Dithiothreitol/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Eukaryotic Initiation Factors
MH  - Immunosuppressive Agents/pharmacology
MH  - Interleukin-2/pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Lymphocyte Activation
MH  - Lymphoma, T-Cell
MH  - Mice
MH  - Morpholines/*pharmacology
MH  - Phosphatidylinositol 3-Kinases
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation/drug effects
MH  - Phosphotransferases (Alcohol Group Acceptor)/*antagonists & 
      inhibitors/genetics/isolation & purification
MH  - Polyenes/pharmacology
MH  - *Protein Kinases
MH  - Rats
MH  - Recombinant Fusion Proteins/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus
MH  - T-Lymphocytes/immunology
MH  - T-Lymphocytes, Cytotoxic
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Cells, Cultured
MH  - Wortmannin
PMC - PMC452270
EDAT- 1996/10/01 00:00
MHDA- 2001/03/28 10:01
PMCR- 1997/10/01
CRDT- 1996/10/01 00:00
PHST- 1996/10/01 00:00 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1996/10/01 00:00 [entrez]
PHST- 1997/10/01 00:00 [pmc-release]
PST - ppublish
SO  - EMBO J. 1996 Oct 1;15(19):5256-67.