Induction of DNA synthesis and apoptosis in cardiac myocytes by E1A oncoprotein

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Abstract

Beginning during the second half of gestation, increasing numbers of cardiac myocytes withdraw from the cell cycle such that DNA synthesis is no longer detectable in these cells by neonatal day 17 in vivo. The mechanisms that exclude these and other terminally differentiated cells from the cell division cycle are poorly understood. To begin to explore the molecular basis of the barrier to G1/S progression in cardiac myocytes, we used adenoviruses to express wild-type and mutant E1A proteins in primary cultures from embryonic day 20 rats. While most of these cardiac myocytes are ordinarily refractory to DNA synthesis, even in the presence of serum growth factors, expression of wild-type E1A stimulates DNA synthesis in up to 94% or almost all successfully transduced cells. Rather than complete the cell cycle, however, these cells undergo apoptosis. Apoptosis is limited to those cells that engage in DNA synthesis, and the kinetics of the two processes suggest that DNA synthesis precedes apoptosis. Mutations in E1A that disable it from binding Rb and related pocket proteins have little effect on its ability to stimulate DNA synthesis in cardiac myocytes. In contrast, mutants that are defective in binding the cellular protein p300 stimulate DNA synthesis 2.4- 4.1-fold less efficiently, even in the context of retained E1A pocket protein binding. In the absence of E1A pocket protein binding, the usual situation in the cell, loss of p300 binding severely decreases the ability of E1A to stimulate DNA synthesis. These results suggest that the barrier to G1/S progression in cardiac myocytes is mediated, at least in part, by the same molecules that gate the G1/S transition in actively cycling cells, and that p300 or related family members play an important role in this process.

Original languageEnglish (US)
Pages (from-to)325-334
Number of pages10
JournalJournal of Cell Biology
Volume133
Issue number2
DOIs
StatePublished - Apr 1 1996

ASJC Scopus subject areas

  • Cell Biology

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