Regulation of Fas expression by STAT3 and c-Jun is mediated by phosphatidylinositol 3-kinase-AKT signaling.
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.
Ivanov
Vladimir N
VN
Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Krasilnikov
Mikhail
M
Ronai
Ze'ev
Z
D017209:Apoptosis; D015153:Blotting, Western; D002867:Chromones / Q000494:pharmacology; D017931:DNA Primers / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis*
D002867:Chromones; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D008156:Luciferases; D008164:Luminescent Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C494086:STAT3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human