Phenotypic Differentiation without Permanent Cell-Cycle Arrest by Skeletal Myocytes with Deregulated E2F-1

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Abstract
Skeletal muscle terminal differentiation includes expression of muscle cell-specific proteins and concomitant cell-cycle arrest. These two processes require functional retinoblastoma protein (RB). E2F-1 is an RB-associated transcriptional factor and an effector of RB in the regulation of G1 to S-phase transition. Here, we show that proper regulation of E2F-1 is crucial for differentiation-coupled cell-cycle arrest by skeletal myocytes. On induction to differentiate, C2 myoblasts constitutively expressing E2F-1 synthesized muscle cell-specific proteins, fused into myotubes, and upregulated the cdk inhibitor p21. However, unlike control cells, differentiated myocytes expressing exogenous E2F-1 incorporated bromodeoxyuridine into nuclei, indicating S-phase entry. This S-phase entry was accompanied by expression of cyclin A. Our results support the view that RB regulates cell-cycle arrest and muscle cell differentiation through separable mechanisms.