PMID- 11784721
OWN - NLM
STAT- MEDLINE
DCOM- 20020429
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 12
DP  - 2002 Mar 22
TI  - Insulin regulation of insulin-like growth factor-binding protein-1 gene 
      expression is dependent on the mammalian target of rapamycin, but independent of 
      ribosomal S6 kinase activity.
PG  - 9889-95
AB  - Insulin inhibits the expression of the hepatic insulin-like growth factor-binding 
      protein-1 (IGFBP-1) and glucose-6-phosphatase (G6Pase) genes. The signaling 
      pathway that mediates these events requires the activation of 
      phosphatidylinositol 3-kinase, whereas transfection studies have suggested an 
      involvement of Akt (protein kinase B) and FKHR, a transcription factor regulated 
      by Akt. We now demonstrate that insulin repression of endogenous IGFBP-1 gene 
      transcription was blocked by rapamycin or by amino acid starvation. Rapamycin 
      inhibited the mammalian target of rapamycin (mTOR) and the subsequent activation 
      of p70/p85 S6 protein kinase-1 (S6K1) by insulin, whereas amino acid depletion 
      prevented insulin induction of these signaling molecules. Importantly, we 
      demonstrate that insulin regulation of the thymine-rich insulin response element 
      of the IGFBP-1 promoter was also inhibited by rapamycin. However, sustained 
      activation of S6K1 did not repress this promoter. In addition, rapamycin did not 
      affect insulin regulation of G6Pase expression or Akt activation. We propose that 
      these observations indicate that an mTOR-dependent, but S6K-independent mechanism 
      regulates the suppression of IGFBP-1 (but not G6Pase) gene expression by insulin. 
      Therefore, although the insulin-responsive sequence of the G6Pase gene promoter 
      is related to that of the IGFBP-1 promoter, the signaling pathways that mediate 
      suppression of these genes are distinct.
FAU - Patel, Satish
AU  - Patel S
AD  - Division of Cellular Signalling, School of Life Sciences, Wellcome Trust 
      Biocentre/Medical Sciences Institute Complex, Dow Street, University of Dundee, 
      Dundee DD1 5EH, United Kingdom.
FAU - Lochhead, Pamela A
AU  - Lochhead PA
FAU - Rena, Graham
AU  - Rena G
FAU - Fumagalli, Stefano
AU  - Fumagalli S
FAU - Pende, Mario
AU  - Pende M
FAU - Kozma, Sara C
AU  - Kozma SC
FAU - Thomas, George
AU  - Thomas G
FAU - Sutherland, Calum
AU  - Sutherland C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20020109
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (DNA, Complementary)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 1)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 3.1.- (Ribonucleases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Amino Acid Motifs
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line
MH  - Culture Media, Serum-Free/pharmacology
MH  - DNA, Complementary/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Insulin/*metabolism
MH  - Insulin-Like Growth Factor Binding Protein 1/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Plasmids/metabolism
MH  - Precipitin Tests
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - RNA/metabolism
MH  - Rats
MH  - Ribonucleases/metabolism
MH  - Ribosomal Protein S6 Kinases/*metabolism
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - Time Factors
MH  - Transcription, Genetic
MH  - Transfection
MH  - Tumor Cells, Cultured
EDAT- 2002/01/11 10:00
MHDA- 2002/05/01 10:01
CRDT- 2002/01/11 10:00
PHST- 2002/01/11 10:00 [pubmed]
PHST- 2002/05/01 10:01 [medline]
PHST- 2002/01/11 10:00 [entrez]
AID - S0021-9258(19)36112-5 [pii]
AID - 10.1074/jbc.M109870200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Mar 22;277(12):9889-95. doi: 10.1074/jbc.M109870200. Epub 2002 
      Jan 9.