PMID- 16455781
OWN - NLM
STAT- MEDLINE
DCOM- 20060523
LR  - 20221207
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 147
IP  - 5
DP  - 2006 May
TI  - Regulation of hepatic insulin-like growth factor-binding protein-1 gene 
      expression by insulin: central role for mammalian target of rapamycin independent 
      of forkhead box O proteins.
PG  - 2383-91
AB  - The expression of IGF-binding protein-1 (IGFBP-1) is induced in rat liver by 
      dexamethasone and glucagon and is completely inhibited by 100 nM insulin. Various 
      studies have implicated phosphatidylinositol 3-kinase, protein kinase B (Akt), 
      phosphorylation of the transcription factors forkhead in rhabdomyosarcoma 1 
      (Foxo1)/Foxo3, and the mammalian target of rapamycin (mTOR) in insulin's effect. 
      In this study we examined insulin regulation of IGFBP-1 in both subconfluent and 
      confluent hepatocytes. In subconfluent hepatocytes, insulin inhibition of IGFBP-1 
      mRNA levels was blocked by inhibiting PI3 kinase activation, and there was a 
      corresponding inhibition of Foxo1/Foxo3 phosphorylation. In these same cells, 
      inhibition of the insulin effect by rapamycin occurred in the presence of 
      insulin-induced Foxo1/Foxo3 phosphorylation. In confluent hepatocytes, insulin 
      could not activate the phosphatidylinositol 3-kinase (PI3 kinase)-Akt-Foxo1/Foxo3 
      pathway, but still inhibited IGFBP-1 gene expression in an mTOR-dependent manner. 
      In subconfluent hepatocytes, the serine/threonine phosphatase inhibitor okadaic 
      acid (100 nM) partially inhibited IGFBP-1 gene expression by 40%, but did not 
      produce phosphorylation of either Akt or Foxo proteins. In contrast, 1 nm insulin 
      inhibited the IGFBP-1 mRNA level by 40% and correspondingly activated Akt and 
      Foxo1/Foxo3 phosphorylation to a level comparable to that observed with 100 nM 
      insulin. These results suggest a potential role for a serine/threonine 
      phosphatase(s) in the regulation of IGFBP-1 gene transcription, which is not 
      downstream of mTOR and is independent of Akt. In conclusion, we have found that 
      in rat liver, insulin inhibition of IGFBP-1 mRNA levels can occur in the absence 
      of the phosphorylation of Foxo1/Foxo3, whereas activation of the mTOR pathway is 
      both necessary and sufficient.
FAU - Mounier, Catherine
AU  - Mounier C
AD  - Polypeptide Hormone Laboratory, Faculty of Medicine, McGill University, Montreal, 
      Quebec, Canada.
FAU - Dumas, Victor
AU  - Dumas V
FAU - Posner, Barry I
AU  - Posner BI
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060202
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Androstadienes)
RN  - 0 (FOXO3 protein, rat)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Insulin)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 1)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Foxo1 protein, rat)
RN  - 1W21G5Q4N2 (Okadaic Acid)
RN  - 63231-63-0 (RNA)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Dexamethasone/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/metabolism
MH  - *Gene Expression Regulation
MH  - Genes, Dominant
MH  - Glucagon/metabolism
MH  - Hepatocytes/metabolism
MH  - Insulin/*metabolism
MH  - Insulin-Like Growth Factor Binding Protein 1/*biosynthesis/*genetics/metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - Nerve Tissue Proteins/metabolism
MH  - Okadaic Acid/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA/metabolism
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Swine
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - Wortmannin
EDAT- 2006/02/04 09:00
MHDA- 2006/05/24 09:00
CRDT- 2006/02/04 09:00
PHST- 2006/02/04 09:00 [pubmed]
PHST- 2006/05/24 09:00 [medline]
PHST- 2006/02/04 09:00 [entrez]
AID - en.2005-0902 [pii]
AID - 10.1210/en.2005-0902 [doi]
PST - ppublish
SO  - Endocrinology. 2006 May;147(5):2383-91. doi: 10.1210/en.2005-0902. Epub 2006 Feb 
      2.