PMID- 17284572
OWN - NLM
STAT- MEDLINE
DCOM- 20070730
LR  - 20191210
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 292
IP  - 6
DP  - 2007 Jun
TI  - The rapid activation of protein synthesis by growth hormone requires signaling 
      through mTOR.
PG  - E1647-55
AB  - An important function of growth hormone (GH) is to promote cell and tissue 
      growth, and a key component of these effects is the stimulation of protein 
      synthesis. In this study, we demonstrate that, in H4IIE hepatoma cells, GH 
      acutely activated protein synthesis through signaling via the mammalian target of 
      rapamycin (mTOR) and specifically through the rapamycin-sensitive mTOR complex 1 
      (mTORC1). GH treatment enhanced the phosphorylation of two targets of mTOR 
      signaling, 4E-BP1 and ribosomal protein S6. Phosphorylation of S6 and 4E-BP1 was 
      maximal at 30-45 min and 10-20 min after GH stimulation, respectively. Both 
      proteins modulate components of the translational machinery. The GH-induced 
      phosphorylation of 4E-BP1 led to its dissociation from eIF4E and increased 
      binding of eIF4E to eIF4G to form (active) eIF4F complexes. The ability of GH to 
      stimulate the phosphorylation of S6 and 4E-BP1 was blocked by rapamycin. GH also 
      led to the dephosphorylation of a third translational component linked to mTORC1, 
      the elongation factor eEF2. Its regulation followed complex biphasic kinetics, 
      both phases of which required mTOR signaling. GH rapidly activated both the MAP 
      kinase (ERK) and PI 3-kinase pathways. Signaling through PI 3-kinase alone was, 
      however, sufficient to activate the downstream mTORC1 pathway. Consistent with 
      this, GH increased the phosphorylation of TSC2, an upstream regulator of mTORC1, 
      at sites that are targets for Akt/PKB. Finally, the activation of overall protein 
      synthesis by GH in H4IIE cells was essentially completely inhibited by wortmannin 
      or rapamycin. These results demonstrate for the first time that mTORC1 plays a 
      major role in the rapid activation of protein synthesis by GH.
FAU - Hayashi, Amanda A
AU  - Hayashi AA
AD  - Institute of Food Nutrition and Human Health, Massey University, and Metabolism 
      and Microbial Genomics Section, AgResearch Limited, Palmerston North, New 
      Zealand.
FAU - Proud, Christopher G
AU  - Proud CG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070206
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Carrier Proteins)
RN  - 0 (Crtc1 protein, rat)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Eukaryotic Initiation Factor-4F)
RN  - 0 (Eukaryotic Initiation Factor-4G)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Peptide Elongation Factor 2)
RN  - 0 (Phosphoproteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Ribosomal Protein S6)
RN  - 0 (Transcription Factors)
RN  - 9002-72-6 (Growth Hormone)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/metabolism
MH  - Cell Line, Tumor
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Eukaryotic Initiation Factor-4F/biosynthesis
MH  - Eukaryotic Initiation Factor-4G/metabolism
MH  - Growth Hormone/antagonists & inhibitors/*pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Kinetics
MH  - Peptide Elongation Factor 2/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Biosynthesis/*drug effects
MH  - Rats
MH  - Recombinant Proteins/pharmacology
MH  - Ribosomal Protein S6/metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/pharmacology
MH  - Time Factors
MH  - Transcription Factors/*metabolism
EDAT- 2007/02/08 09:00
MHDA- 2007/07/31 09:00
CRDT- 2007/02/08 09:00
PHST- 2007/02/08 09:00 [pubmed]
PHST- 2007/07/31 09:00 [medline]
PHST- 2007/02/08 09:00 [entrez]
AID - 00674.2006 [pii]
AID - 10.1152/ajpendo.00674.2006 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1647-55. doi: 
      10.1152/ajpendo.00674.2006. Epub 2007 Feb 6.