Adenoviral delivery of E2F-1 directs cell cycle reentry and p53- independent apoptosis in postmitotic adult myocardium in vivo

Ramtin Agah, Lorrie A. Kirshenbaum, Maha Abdellatif, Luan Truong, Subendu Chakraborty, Lloyd H. Michael, Michael D. Schneider

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

Abstract

Irreversible exit from the cell cycle precludes the ability of cardiac muscle cells to increase cell number after infarction. Using adenoviral E1A, we previously demonstrated dual pocket protein- and p300-dependent pathways in neonatal rat cardiac myocytes, and have proven that E2F-1, which occupies the Rb pocket, suffices for these actions of E1A. By contrast, the susceptibility of adult ventricular cells to vital delivery of exogenous cell cycle regulators has not been tested, in vitro or in vivo. In cultured adult ventricular myocytes, adenoviral gene transfer of E2F-1 induced expression of proliferating cell nuclear antigen, cyclin-dependent protein kinase 4, cell division cycle 2 kinase, DNA synthesis, and apoptosis. In vivo, adenoviral delivery of E2F-1 by direct injection into myocardium induced DNA synthesis, shown by 5'-bromodeoxyuridine incorporation, and accumulation in G2/M, by image analysis of Feulgen-stained nuclei. In p53(-/-) mice, the prevalence of G1 exit was more than twofold greater; however, E2F-1 evoked apoptosis and rapid mortality comparably in both backgrounds. Thus, the differential effects of E2F-1 on G1 exit in wild-type versus p53-deficient mice illustrate the combinatorial power of vital gene delivery to genetically defined recipients: E2F-1 can override the G1/S checkpoint in postmitotic ventricular myocytes in vitro and in vivo, but leads to apoptosis even in p53(-/-) mice.

Original languageEnglish (US)
Pages (from-to)2722-2728
Number of pages7
JournalJournal of Clinical Investigation
Volume100
Issue number11
DOIs
StatePublished - Dec 1 1997

Keywords

  • Adenovirus
  • Cardiac muscle
  • Cell cycle
  • E2F-1
  • P53

ASJC Scopus subject areas

  • Medicine(all)

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