E2F-1 regulates expression of FOXO1 and FOXO3a.
E2F and FOXO transcription factors both play a role in neuronal apoptosis. In addition, both E2F-induced apoptosis and FOXO function are inhibited by the kinase Akt. We therefore tested whether FOXO is downstream of E2F-1 during neuronal apoptosis. We found that expression of endogenous FOXO1 and FOXO3a is induced by E2F-1. The presence of putative E2F binding sites in the promoters of both genes suggested that FOXO genes are direct targets of E2F-1. Indeed, a 4-hydroxytamoxifen activated E2F-1-ER fusion protein induced FOXO expression in the presence of cycloheximide. Moreover, E2F-1 activated the FOXO1 promoter in transient reporter assays, and E2F-1-ER as well as endogenous E2F bound to the FOXO1 promoter in vivo. Yet, E2F-1-mediated apoptosis of differentiated PC12 cells after withdrawal of NGF was not accompanied by changes in FOXO expression, indicating that no transcriptional induction of FOXO occurs during E2F-1-dependent neuronal apoptosis. In summary, our data identify E2F-1 as a first transcription factor regulating FOXO expression, providing a link between E2F and FOXO proteins in the control of cell fate.
Nowak
Katrin
K
Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
Killmer
Katrin
K
Gessner
Christine
C
Lutz
Werner
W
D000818:Animals; D017209:Apoptosis; D050687:E2F1 Transcription Factor / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D051381:Rats; D000071161:Forkhead Box Protein O1
D050687:E2F1 Transcription Factor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; C493755:E2f1 protein, rat; C499515:FOXO3 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1