PMID- 9852118
OWN - NLM
STAT- MEDLINE
DCOM- 19990126
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 51
DP  - 1998 Dec 18
TI  - Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 
      adipocytes.
PG  - 34496-501
AB  - Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP 
      by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of 
      insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a 
      downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. 
      To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein 
      kinase activity of mTOR was measured in an immune complex assay with recombinant 
      PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 
      3'-5'-monophosphate (CPT-cAMP) prevented the activation of mTOR by insulin in 
      adipocytes, but neither agent affected mTOR activity when added directly to the 
      immunopurified protein. In contrast, the cAMP phosphodiesterase inhibitor, 
      theophylline, inhibited mTOR activity not only when added to intact adipocytes 
      but also when added to immunopurified mTOR in vitro, demonstrating that certain 
      methylxanthines are able to inhibit mTOR independently of increasing cAMP. 
      Forskolin and CPT-cAMP blocked the effect of insulin on increasing mTOR 
      phosphorylation, which was assessed using mTAb1, an antibody whose binding is 
      inhibited by phosphorylation of mTOR. Although the mTAb1 epitope contains a 
      consensus site for protein kinase B, neither agent inhibited the activation of 
      protein kinase B produced by insulin. These findings support the interpretation 
      that increasing cAMP attenuates the effects of insulin on PHAS-I, p70(S6K), and 
      other downstream targets of the mTOR signaling pathway by inhibiting the 
      phosphorylation and activation of mTOR.
FAU - Scott, P H
AU  - Scott PH
AD  - Department of Pharmacology, University of Virginia School of Medicine, 
      Charlottesville, Virginia 22908, USA.
FAU - Lawrence, J C Jr
AU  - Lawrence JC Jr
LA  - eng
GR  - AR41180/AR/NIAMS NIH HHS/United States
GR  - DK28312/DK/NIDDK NIH HHS/United States
GR  - DK52753/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Insulin)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Thionucleotides)
RN  - 1F7A44V6OU (Colforsin)
RN  - 41941-66-6 (8-((4-chlorophenyl)thio)cyclic-3',5'-AMP)
RN  - C137DTR5RG (Theophylline)
RN  - E0399OZS9N (Cyclic AMP)
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 (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  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 3T3 Cells
MH  - Adaptor Proteins, Signal Transducing
MH  - Adipocytes/cytology/drug effects/*metabolism
MH  - Amino Acid Sequence
MH  - Animals
MH  - *Carrier Proteins
MH  - Cell Cycle Proteins
MH  - Colforsin/*pharmacology
MH  - Cyclic AMP/analogs & derivatives/*metabolism/pharmacology
MH  - Eukaryotic Initiation Factors
MH  - Immunoassay
MH  - Insulin/pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Mice
MH  - Molecular Sequence Data
MH  - Peptide Fragments/chemistry/immunology
MH  - Peptide Mapping
MH  - Phosphoproteins/*chemistry/*metabolism
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - *Protein Kinases
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/analysis/chemistry/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Rats
MH  - Recombinant Proteins/metabolism
MH  - Repressor Proteins/metabolism
MH  - Sequence Alignment
MH  - Sequence Homology, Amino Acid
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Theophylline/pharmacology
MH  - Thionucleotides/pharmacology
EDAT- 1998/12/16 16:59
MHDA- 2001/03/28 10:01
CRDT- 1998/12/16 16:59
PHST- 1998/12/16 16:59 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1998/12/16 16:59 [entrez]
AID - S0021-9258(19)88478-8 [pii]
AID - 10.1074/jbc.273.51.34496 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 Dec 18;273(51):34496-501. doi: 10.1074/jbc.273.51.34496.