Reference : Akt modulates STAT3-mediated gene expression through a FKHR (FOXO1a)-dependent mechanism
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Akt modulates STAT3-mediated gene expression through a FKHR (FOXO1a)-dependent mechanism
Kortylewski, M. [> >]
Feld, F. [> >]
Krüger, K. D. [> >]
Bahrenberg, G. [> >]
Roth, R. A. [> >]
Joost, H. G. [> >]
Heinrich, P. C. [> >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Barthel, A. [> >]
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
Yes (verified by ORBilu)
[en] Cell Line ; Trans-Activators ; Trans-Activation (Genetics) ; Signal Transduction ; STAT3 Transcription Factor ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins ; Protein-Tyrosine Kinases ; Protein-Serine-Threonine Kinases ; Mutation ; Interleukin-6 ; Humans ; Forkhead Transcription Factors ; DNA-Binding Proteins ; Transcription Factors
[en] The phosphatidylinositol 3-kinase/Akt pathway plays an important role in the signaling of insulin and other growth factors, which reportedly attenuate the interleukin-6 (IL-6)-mediated stimulation of acute phase plasma protein genes. We investigated the effect of the protein kinase Akt on IL-6-mediated transcriptional activation. The transient expression of constitutively active Akt inhibited the IL-6-dependent activity of the alpha(2)-macroglobulin promoter in HepG2 cells, whereas expression of an inactive mutant of phosphatidylinositol-dependent kinase 1 had the opposite effect. Since Akt is known to regulate gene expression through inactivation of the transcription factor FKHR (forkhead in rhabdomyosarcoma), we examined the effect of FKHR on STAT3-mediated transcriptional regulation. Indeed, the overexpression of FKHR specifically enhanced the activity of STAT3-dependent promoters but not that of a STAT5-responsive promoter. The effect of FKHR required the presence of functional STAT3 and was abrogated by the expression of dominant negative STAT3 mutants. Furthermore, FKHR and STAT3 were shown to coimmunoprecipitate and to colocalize in the nuclear regions of IL-6-treated HepG2 cells. Our results indicate that FKHR can modulate the IL-6-induced transcriptional activity by acting as a coactivator of STAT3.

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