title: Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis.
abstract: Proliferation of mammalian cardiomyocytes ceases around birth when a transition from hyperplastic to hypertrophic myocardial growth occurs. Previous studies demonstrated that directed expression of the transcription factor E2F1 induces S-phase entry in cardiomyocytes along with stimulation of programmed cell death. Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression. Although both E2F2 and E2F4 induced S-phase entry only directed expression of E2F2 resulted in mitotic cell division of cardiomyocytes. Expression of E2F5 or a control LacZ-Adenovirus had no effects on cell cycle progression. Quantitative real time PCR revealed that E2F1, E2F2, E2F3, and E2F4 alleviate G0 arrest by induction of cyclinA and E cyclins. Furthermore, directed expression of E2F1, E2F3, and E2F5 led to a transcriptional activation of several proapoptotic genes, which were mitigated by E2F2 and E2F4. Our finding that expression of E2F2 induces cell division of cardiomyocytes along with a suppression of proapoptotic genes might open a new access to improve the regenerative capacity of cardiomyocytes.
authors.affiliation: Institute of Physiological Chemistry, University of Halle-Wittenberg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Ebelt
authors.forename: Nadine
authors.initials: N
authors.lastname: Hufnagel
authors.forename: Petra
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Herbert
authors.initials: H
authors.lastname: Neuhaus
authors.forename: Praveen
authors.initials: P
authors.lastname: Gajawada
authors.forename: Andreas
authors.initials: A
authors.lastname: Simm
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Werdan
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D016895:Culture Media, Serum-Free; D016213:Cyclins / Q000502:physiology; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D020287:In Situ Nick-End Labeling; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000502:physiology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016160:Retinoblastoma Protein / Q000502:physiology; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016196:S Phase / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; C493754:E2f1 protein, mouse; C493755:E2f1 protein, rat; C493763:E2f4 protein, mouse; D009687:Nuclear Proteins; C430714:Plcl1 protein, rat; D011506:Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors