Human E2F-1 reactivates cell cycle progression in ventricular myocytes and represses cardiac gene transcription.
The "pocket" protein- and p300-binding domains of E1A mediate alternative pathways that, independently, provoke S phase reentry in ventricular muscle cells and repress cardiac-specific transcription. In the present study, we utilized recombinant adenovirus to deliver mammalian E2F-1, whose release from pocket proteins may underlie effects of E1A and mitogenic signaling. Like E1A, E2F-1 proved cytotoxic in the absence of E1B. Used along with E1B to avert apoptosis, E2F-1 inhibited the cardiac and skeletal alpha-actin promoters, serum response factor abundance, and sarcomeric actin biosynthesis, while inducing DNA synthesis and proliferating cell nuclear antigen. Image analysis of Feulgen-stained nuclei corroborated a parallel increase in DNA content, with accumulation in G2/M. Thus, E2F-1 suffices for all observed actions of E1A in cardiac myocytes.
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg.
L A
LA
Kirshenbaum
M
M
Abdellatif
S
S
Chakraborty
M D
MD
Schneider
D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006352:Heart Ventricles; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493755:E2f1 protein, rat; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors