PMID- 18701653
OWN - NLM
STAT- MEDLINE
DCOM- 20081201
LR  - 20211020
IS  - 0363-6143 (Print)
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Linking)
VI  - 295
IP  - 4
DP  - 2008 Oct
TI  - TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not 
      AKT-Foxo1/3 signaling.
PG  - C986-93
LID - 10.1152/ajpcell.00041.2008 [doi]
AB  - Murine models of starvation-induced muscle atrophy demonstrate that reduced 
      protein kinase B (AKT) function upregulates the atrophy-related gene 
      atrogin-1/MAFbx (atrogin). The mechanism involves release of inhibition of 
      Forkhead transcription factors, namely Foxo1 and Foxo3. Elevated atrogin mRNA 
      also corresponds with elevated TNF in inflammatory catabolic states, including 
      cancer and chronic heart failure. Exogenous tumor necrosis factor (TNF) increases 
      atrogin mRNA in vivo and in vitro. We used TNF-treated C2C12 myotubes to test the 
      hypothesis that AKT-Foxo1/3 signaling mediates TNF regulation of atrogin mRNA. 
      Here we confirm that exposure to TNF increases atrogin mRNA (+125%). We also 
      confirm that canonical AKT-mediated regulation of atrogin is active in C2C12 
      myotubes. Inhibition of phosphoinositol-3 kinase (PI3K)/AKT signaling with 
      wortmannin reduces AKT phosphorylation (-87%) and increases atrogin mRNA (+340%). 
      Activation with insulin-like growth factor (IGF) increases AKT phosphorylation 
      (+126%) and reduces atrogin mRNA (-15%). Although AKT regulation is intact, our 
      data suggest it does not mediate TNF effects on atrogin. TNF increases AKT 
      phosphorylation (+50%) and stimulation of AKT with IGF does not prevent TNF 
      induction of atrogin mRNA. Nor does TNF appear to signal through Foxo1/3 
      proteins. TNF has no effect on Foxo1/3 mRNA or Foxo1/3 nuclear localization. 
      Instead, TNF increases nuclear Foxo4 protein (+55%). Small interfering RNA oligos 
      targeted to two distinct regions of Foxo4 mRNA reduce the TNF-induced increase in 
      atrogin mRNA (-34% and -32%). We conclude that TNF increases atrogin mRNA 
      independent of AKT via Foxo4. These results suggest a mechanism by which 
      inflammatory catabolic states may persist in the presence of adequate growth 
      factors and nutrition.
FAU - Moylan, Jennifer S
AU  - Moylan JS
AD  - Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0298, 
      USA. jennifer.moylan@uky.edu
FAU - Smith, Jeffrey D
AU  - Smith JD
FAU - Chambers, Melissa A
AU  - Chambers MA
FAU - McLoughlin, Thomas J
AU  - McLoughlin TJ
FAU - Reid, Michael B
AU  - Reid MB
LA  - eng
GR  - HL-59878/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080813
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (FoxO3 protein, mouse)
RN  - 0 (FoxO4 protein, mouse)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Muscle Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - 0 (Somatomedins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.3.2.27 (Fbxo32 protein, mouse)
RN  - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Forkhead Box Protein O1
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Gene Expression Regulation
MH  - Mice
MH  - Muscle Proteins/genetics/*metabolism
MH  - Myoblasts/drug effects/metabolism
MH  - Protein Isoforms
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - SKP Cullin F-Box Protein Ligases/genetics/*metabolism
MH  - Signal Transduction
MH  - Somatomedins/metabolism
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC2575831
EDAT- 2008/08/15 09:00
MHDA- 2008/12/17 09:00
PMCR- 2009/10/01
CRDT- 2008/08/15 09:00
PHST- 2008/08/15 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/08/15 09:00 [entrez]
PHST- 2009/10/01 00:00 [pmc-release]
AID - 00041.2008 [pii]
AID - C-00041-2008 [pii]
AID - 10.1152/ajpcell.00041.2008 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2008 Oct;295(4):C986-93. doi: 
      10.1152/ajpcell.00041.2008. Epub 2008 Aug 13.