Document Detail

Regulation of Fas expression by STAT3 and c-Jun is mediated by phosphatidylinositol 3-kinase-AKT signaling.
MedLine Citation:
PMID:  11733515     Owner:  NLM     Status:  MEDLINE    
Cooperation between STAT3 and c-Jun results in suppression of Fas Receptor (FasR) transcription, which is often seen in advanced human tumors. To identify requirements for STAT3-Jun cooperation, we elucidated the role of protein kinases that affect both transcription factors. The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway was found capable of down-regulating both STAT3- and c-Jun-dependent transcription, resulting in derepression of FasR transcription. Conversely, inhibition of PI3K-AKT signaling via the specific pharmacological inhibitor LY294002 up-regulated AP1/Jun- and STAT-dependent transcriptional activities, resulting in suppression of the FasR promoter activities and decreased FasR surface expression. PI3K-AKT's ability to affect FasR transcription was not observed in c-jun null fibroblasts, suggesting that c-Jun is required for PI3K/AKT-mediated regulation of FasR transcription. Interestingly, the dominant negative form of Rac1 (RacN17) was also efficient in relieving FasR expression, suggesting that the increase in FasR expression following AKT stimuli could be mediated via AKT ability to elicit suppression of Rac1, which in turn decreases JNK activities and c-Jun phosphorylation. Overall, our findings demonstrate that through its negative effects on both c-Jun and STAT3, the PI3K-AKT pathway disrupts cooperation between c-Jun and STAT3, which is required for silencing the FasR promoter, resulting in increased expression of surface FasR and concomitant sensitization to FasL-mediated programmed cell death.
Vladimir N Ivanov; Mikhail Krasilnikov; Ze'ev Ronai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2001-12-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Feb 
Date Detail:
Created Date:  2002-02-11     Completed Date:  2002-03-21     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4932-44     Citation Subset:  IM    
Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
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MeSH Terms
Antigens, CD95 / biosynthesis*
Blotting, Western
Chromones / pharmacology
DNA Primers / pharmacology
DNA-Binding Proteins / metabolism*
Enzyme Inhibitors / pharmacology
Flow Cytometry
Gene Expression Regulation*
Genes, Dominant
Green Fluorescent Proteins
Luciferases / metabolism
Luminescent Proteins / metabolism
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / metabolism*
Plasmids / metabolism
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-jun / metabolism*
STAT3 Transcription Factor
Signal Transduction*
Trans-Activators / metabolism*
Transcription, Genetic
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / metabolism
Grant Support
Reg. No./Substance:
0/Antigens, CD95; 0/Chromones; 0/DNA Primers; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/Luminescent Proteins; 0/Morpholines; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-jun; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Trans-Activators; 0/Tumor Necrosis Factor-alpha; 147336-22-9/Green Fluorescent Proteins; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 1.13.12.-/Luciferases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC protein, human; EC Kinases; EC Proteins c-akt

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