The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors.
FOXO (Forkhead box O) transcription factors induce cell growth arrest and apoptosis, which can be prevented by FOXO phosphorylation by AKT in response to growth factors such as platelet-derived growth factors (PDGF) and insulin-like growth factor I (IGF-I). In addition to this well characterized post-translational modification, we showed that FOXO1, FOXO3, and FOXO4 were also regulated at the transcriptional level. PDGF, fibroblast growth factors (FGF), and IGF-I repressed the expression of FOXO genes in human fibroblasts. This process was sensitive to phosphatidylinositol 3-kinase inhibition by LY294002. FOXO1-specific shRNA decreased FOXO1 mRNA expression and enhanced fibroblast proliferation, mimicking the effects of growth factors. Conversely, ectopic FOXO3 activation blocked the proliferation of fibroblasts and induced the expression of FOXO1, FOXO4, and p27-KIP1. Using luciferase reporter assays and chromatin immunoprecipitations, we identified a conserved FOXO-binding site in the promoter of the FOXO1 gene, which was required for regulation by PDGF, and mediated the up-regulation of FOXO1 by itself and by FOXO3. Altogether, our results suggest that the expression of FOXO1 and FOXO4 genes is stimulated by FOXO3 and possibly by other FOXO factors in a positive feedback loop, which is disrupted by growth factors.
Essaghir
Ahmed
A
De Duve Institute, Université Catholique de Louvain, BE-1200 Brussels, Belgium.
Dif
Nicolas
N
Marbehant
Catherine Y
CY
Coffer
Paul J
PJ
Demoulin
Jean-Baptiste
JB
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human