PMID- 15632117
OWN - NLM
STAT- MEDLINE
DCOM- 20050513
LR  - 20210206
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 13
DP  - 2005 Apr 1
TI  - FOXO1 functions as a master switch that regulates gene expression necessary for 
      tumor necrosis factor-induced fibroblast apoptosis.
PG  - 12096-102
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and 
      pro-apoptotic mediator that plays an important role in several normal and disease 
      processes. TNF-induced cell death is one of the principal mechanisms by which 
      cells are removed. Although TNF-mediated apoptosis has been the subject of 
      intense investigation, the transcriptional mechanisms through which it promotes 
      apoptosis are not well understood and, paradoxically, the archetypal TNF-induced 
      nuclear factor NFkappaB is anti-apoptotic. To identify a potential master 
      transcriptional regulator of apoptosis, we examined an array of 
      TNF-alpha-activated transcription factors. Fork-head box class-O 1 (FOXO1) was 
      strongly activated, which was confirmed in vitro and in vivo by electrophoretic 
      mobility shift assay. The central importance of FOXO1 was established in 
      experiments with small inhibitory RNA (siRNA) that specifically silenced FOXO1. 
      When FOXO1 was silenced, fibroblast apoptosis was reduced 76%. Other siRNAs that 
      partially inhibited FOXO1 expression were proportionately effective in reducing 
      apoptosis. Transcriptional profiling was then carried out in conjunction with 
      siRNA to establish mechanisms by which FOXO1 modulated apoptosis. In the absence 
      of FOXO1, TNF-alpha failed to up-regulate a large number of pro-apoptotic gene 
      families including ligands, receptors, adapter molecules, mitochondrial proteins, 
      and caspases. siRNA silencing also blocked down-regulation of anti-apoptotic 
      genes. These results indicate that TNF induces activation of the FOXO1 
      transcription factor, which acts as a master switch to control apoptosis.
FAU - Alikhani, Mani
AU  - Alikhani M
AD  - Department of Periodontology and Oral Biology, Boston University School of Dental 
      Medicine, Boston, Massachusetts 02118, USA.
FAU - Alikhani, Zoubin
AU  - Alikhani Z
FAU - Graves, Dana T
AU  - Graves DT
LA  - eng
GR  - R01DE07559/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050104
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Ligands)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 63231-63-0 (RNA)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/metabolism/*physiology
MH  - Down-Regulation
MH  - Fibroblasts/metabolism/*pathology
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors
MH  - *Gene Expression Regulation
MH  - Gene Silencing
MH  - Humans
MH  - Ligands
MH  - Mice
MH  - Mitochondria/metabolism
MH  - NF-kappa B/metabolism
MH  - RNA/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction
MH  - Time Factors
MH  - Transcription Factors/metabolism/*physiology
MH  - Transcription, Genetic
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - Up-Regulation
EDAT- 2005/01/06 09:00
MHDA- 2005/05/14 09:00
CRDT- 2005/01/06 09:00
PHST- 2005/01/06 09:00 [pubmed]
PHST- 2005/05/14 09:00 [medline]
PHST- 2005/01/06 09:00 [entrez]
AID - S0021-9258(19)60531-4 [pii]
AID - 10.1074/jbc.M412171200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Apr 1;280(13):12096-102. doi: 10.1074/jbc.M412171200. Epub 2005 
      Jan 4.