PMID- 11278364
OWN - NLM
STAT- MEDLINE
DCOM- 20010524
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 14
DP  - 2001 Apr 6
TI  - Rapamycin-insensitive regulation of 4e-BP1 in regenerating rat liver.
PG  - 10943-51
AB  - In cultured cells, growth factor-induced phosphorylation of two translation 
      modulators, p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 
      (4E-BP1), is blocked by nanomolar concentrations of the immunosuppressant 
      rapamycin. Rapamycin also attenuates liver regeneration after partial 
      hepatectomy, but it is not known if this growth-suppressive effect is due to 
      dephosphorylation of p70 S6 kinase and/or 4E-BP1. We found that partial 
      hepatectomy induced a transient increase in liver p70 S6 kinase activity and 
      4E-BP1 phosphorylation as compared with sham-operated rats. The amount of p70 S6 
      kinase protein in regenerating liver did not increase, but active kinase from 
      partially hepatectomized animals was highly phosphorylated. Phosphorylated 4E-BP1 
      from regenerating liver was unable to form an inhibitory complex with initiation 
      factor 4E. Rapamycin blocked the activation of p70 S6 kinase in response to 
      partial hepatectomy in a dose-dependent manner, but 4E-BP1 phosphorylation was 
      not inhibited. By contrast, functional phosphorylation of 4E-BP1 induced by 
      injection of cycloheximide or growth factors was partially reversed by the drug. 
      The mammalian target of rapamycin (mTOR) has been proposed to directly 
      phosphorylate 4E-BP1. Western blot analysis using phospho-specific antibodies 
      showed that phosphorylation of Thr-36/45 and Ser-64 increased in response to 
      partial hepatectomy in a rapamycin-resistant manner. Thus, rapamycin inhibits p70 
      S6 kinase activation and liver regeneration, but not functional phosphorylation 
      of 4E-BP1, in response to partial hepatectomy. These results indicate that the 
      effect of rapamycin on 4E-BP1 function in vivo can be significantly different 
      from its effect in cultured cells.
FAU - Jiang, Y P
AU  - Jiang YP
AD  - Departments of Pharmacology and Medicine, University of Texas Health Science 
      Center and the Research Service, Audie L. Murphy Memorial Veterans Hospital, San 
      Antonio, Texas 78229, USA.
FAU - Ballou, L M
AU  - Ballou LM
FAU - Lin, R Z
AU  - Lin RZ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20010125
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *Carrier Proteins
MH  - Immunosuppressive Agents/*pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - *Liver Regeneration
MH  - Male
MH  - Phosphoproteins/*physiology
MH  - Phosphorylation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribosomal Protein S6 Kinases/physiology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
EDAT- 2001/03/30 10:00
MHDA- 2001/06/02 10:01
CRDT- 2001/03/30 10:00
PHST- 2001/03/30 10:00 [pubmed]
PHST- 2001/06/02 10:01 [medline]
PHST- 2001/03/30 10:00 [entrez]
AID - S0021-9258(19)34533-8 [pii]
AID - 10.1074/jbc.M007758200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Apr 6;276(14):10943-51. doi: 10.1074/jbc.M007758200. Epub 2001 
      Jan 25.