Abstract
E2F1 and FOXO3 are two transcription factors that have been shown to participate in cellular senescence. Previous report reveals that E2F1 enhanced cellular senescence in human fibroblast cells, while FOXO transcription factors play against senescence by regulation reactive oxygen species scavenging proteins. However, their functional interplay has been unclear. Here we use E2F1 knock-out murine Embryonic fibroblasts (MEFs), knockdown RNAi constructs, and ectopic expression of E2F1 to show that it functions by negatively regulating FOXO3. E2F1 attenuates FOXO3-mediated expression of MnSOD and Catalase without affecting FOXO3 protein stability, subcellular localization, or phosphorylation by Akt. We mapped the interaction between E2F1 and FOXO3 to a region including the DNA binding domain of E2F1 and the C-terminal transcription-activation domain of FOXO3. We propose that E2F1 inhibits FOXO3-dependent transcription by directly binding FOXO3 in the nucleus and preventing activation of its target genes. Moreover, knockdown of the Caenorhabditis elegans E2F1 ortholog efl-1 significantly extends lifespan in a manner that requires the activity of the C. elegans FOXO gene daf-16. We conclude that there is an evolutionarily conserved signaling connection between E2F1 and FOXO3, which regulates cellular senescence and aging by regulating the activity of FOXO3. We speculate that drugs and/or therapies that inhibit this physical interaction might be good candidates for reducing cellular senescence and increasing longevity.
Highlights
E2F transcription factor 1 (E2F1) and FOXO3 are two transcription factors participating in cellular senescence
The proliferation of passage 5 WT murine Embryonic fibroblasts (MEFs) was greatly reduced compared with E2F1 knock-out (E2F1 KO) MEFs, with all cells visualized by Hoechst stained DNA but DNA synthesis was greatly reduced only in WT cells (Fig. 1A, left panel)
The our results show that E2F1 and EFL-1 bind to and inhibit the transcriptional activity of FOXO3 and DAF-16, respectively, to regulate cellular senescence and lifespan and that this function is conserved from nematodes to mammals
Summary
E2F1 and FOXO3 are two transcription factors participating in cellular senescence. Results: E2F1 represses FOXO3 transactivity through interaction. While one member of this family has been identified in C. elegans, DAF-16 [11, 12], four mammalian family members are known This protein family is highly conserved and consists of a DNA binding domain, nuclear localization signal, nuclear export signal, transcriptional activation domain, and numerous sites for various post-translational modifications, which play critical roles in regulating FOXO activity [9, 10]. We demonstrate that E2F1 and FOXO3 physically interact, and that this results in the inhibition of FOXO3 This requirement is conserved across species as we show that reducing levels of efl-1 in C. elegans increase their longevity but only in the presence of functional DAF-16. We conclude that one mechanism through which E2F1 regulates the cell cycle and senescence is by inhibiting the activity of FOXO3
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