Akt modulates STAT3-mediated gene expression through a FKHR (FOXO1a)-dependent mechanism.
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.
Kortylewski
Marcin
M
Institut für Biochemie, RWTH Aachen, 52057 Aachen, Germany.
Feld
Florian
F
Krüger
Klaus-Dieter
KD
Bahrenberg
Gregor
G
Roth
Richard A
RA
Joost
Hans-Georg
HG
Heinrich
Peter C
PC
Behrmann
Iris
I
Barthel
Andreas
A
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt