PMID- 18079193
OWN - NLM
STAT- MEDLINE
DCOM- 20080422
LR  - 20211203
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 149
IP  - 3
DP  - 2008 Mar
TI  - Forkhead box protein O1 negatively regulates skeletal myocyte differentiation 
      through degradation of mammalian target of rapamycin pathway components.
PG  - 1407-14
AB  - The forkhead transcription factor forkhead box protein O1 (FoxO1), a downstream 
      target of phosphatidylinositol 3-kinase/Akt signaling, has been reported to 
      suppress skeletal myocyte differentiation, but the mechanism by which FoxO1 
      regulates myogenesis is not fully understood. We have previously demonstrated 
      that a nutrient-sensing mammalian target of rapamycin (mTOR) pathway controls the 
      autocrine production of IGF-II and the subsequent phosphatidylinositol 
      3-kinase/Akt signaling downstream of IGF-II in myogenesis. Here we report a 
      regulatory loop connecting FoxO1 to the mTOR pathway. Inducible activation of a 
      FoxO1 active mutant in the C2C12 mouse myoblasts blocks myogenic differentiation 
      at an early stage and meanwhile leads to proteasome-dependent degradation of a 
      specific subset of components in the mTOR signaling network, including mTOR, 
      raptor, tuberous sclerosis complex 2, and S6 protein kinase 1. This function of 
      FoxO1 requires new protein synthesis, consistent with the idea that a 
      transcriptional target of FoxO1 may be responsible for the degradation of mTOR. 
      We further show that active FoxO1 inhibits IGF-II expression at the 
      transcriptional activation level, through the modulation of mTOR protein levels. 
      Moreover, the addition of exogenous IGF-II fully rescues myocyte differentiation 
      from FoxO inhibition. Taken together, we propose that the mTOR-IGF-II pathway is 
      a major mediator of FoxO's inhibitory function in skeletal myogenesis.
FAU - Wu, Ai-Luen
AU  - Wu AL
AD  - Department of Cell and Developmental Biology, 601 South Goodwin Avenue, 
      University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
FAU - Kim, Jeong-Ho
AU  - Kim JH
FAU - Zhang, Chongben
AU  - Zhang C
FAU - Unterman, Terry G
AU  - Unterman TG
FAU - Chen, Jie
AU  - Chen J
LA  - eng
GR  - R01 AR048914/AR/NIAMS NIH HHS/United States
GR  - R01 DK041430/DK/NIDDK NIH HHS/United States
GR  - DK41430/DK/NIDDK NIH HHS/United States
GR  - AR48914/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20071213
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxo1 protein, mouse)
RN  - 67763-97-7 (Insulin-Like Growth Factor II)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/genetics/*physiology
MH  - Cell Line
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Insulin-Like Growth Factor II/genetics/metabolism
MH  - Mice
MH  - Muscle Development/genetics/physiology
MH  - Myoblasts, Skeletal/*metabolism/*pathology
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Protein Kinases/genetics/*metabolism
MH  - Signal Transduction/genetics/*physiology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription, Genetic/genetics/physiology
PMC - PMC2275355
EDAT- 2007/12/15 09:00
MHDA- 2008/04/23 09:00
PMCR- 2009/03/01
CRDT- 2007/12/15 09:00
PHST- 2007/12/15 09:00 [pubmed]
PHST- 2008/04/23 09:00 [medline]
PHST- 2007/12/15 09:00 [entrez]
PHST- 2009/03/01 00:00 [pmc-release]
AID - en.2007-1470 [pii]
AID - 3905 [pii]
AID - 10.1210/en.2007-1470 [doi]
PST - ppublish
SO  - Endocrinology. 2008 Mar;149(3):1407-14. doi: 10.1210/en.2007-1470. Epub 2007 Dec 
      13.