Long-term fate of terminally differentiated skeletal muscle cells following E1A-initiated cell cycle reactivation

We have previously shown that E1A reactivates the cell cycle in 'irreversibly' growth arrested, terminally differentiated (TD) cells. The molecular events following E1A-mediated reactivation of TD skeletal muscle cells have been extensively investigated. However, the long-term fate of the reactivated cells has not been directly determined. In this paper, E1A is used to reactivate TD myotubes derived from established cell lines or primary myoblasts. We show that the reactivated muscle cells continue proliferating beyond the end of the first cell cycle and progress through at least a second one. Experiments performed with an inducible E1A/estrogen receptor chimera indicate that the reactivated cell cycle is self-sustained, since E1A is exclusively necessary to reactivate TD cells, but is dispensable for both the continuation of the first cycle and the progression into the following one. Finally, we report that E1A-mediated reactivation of muscle cells results in apoptotic cell death that can be delayed by the antiapoptotic, adenoviral E1B 55 kDa oncogene.