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 altern ative pathways that, independently, provoke S phase reentry in ventric ular muscle cells and repress cardiac-specific transcription, In the p resent 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 absen ce of E1B. Used along with E1B to avert apoptosis, E2F-1 inhibited the cardiac and skeletal alpha-actin promoters, serum response faster abu ndance, and sarcomeric actin biosynthesis, while inducing DNA synthesi s and proliferating cell nuclear antigen. Image analysis of Feulgen-st ained nuclei corroborated a parallel increase in DNA content, with acc umulation in G(2)/M. Thus, E2P-1 suffices for all observed actions of E1A in cardiac myocytes. (C) 1996 Academic Press, Inc.