Current Biology
Volume 9, Issue 9, 6 May 1999, Pages 449-459
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Research Paper
pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation

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Abstract

Background: The onset of differentiation-specific gene expression in skeletal muscle is coupled to permanent withdrawal from the cell cycle. The retinoblastoma tumor-suppressor protein (pRb) is a critical regulator of this process, required for both cell-cycle arrest in G0 phase and high-level expression of late muscle-differentiation markers. Although the cell-cycle defects that are seen in pRb-deficient myocytes can be explained by the well-described function of pRb as a negative regulator of the transition from G1 to S phase, it remains unclear how pRb positively affects late muscle-gene expression.

Results: Here, we show that the myogenic defect in Rb−/− cells corresponds to a deficiency in the activity of the transcription factor MEF2. Without pRb, MyoD induces the accumulation of nuclear-localized MEF2 that is competent to bind DNA yet transcriptionally inert. When pRb is present, MyoD stimulates the function of the MEF2C transcriptional activation domain and the activity of endogenous MEF2-type factors. Co-transfection of MyoD together with an activated form of MEF2C containing the Herpesvirus VP16 transcriptional activation domain partially bypasses the requirement for pRb and induces late muscle-gene expression in replicating cells. This ectopic myogenesis is nevertheless significantly augmented by co-expression of an E2F1–pRb chimeric protein that blocks the cell cycle.

Conclusion: These findings indicate that pRb promotes the expression of late-stage muscle-differentiation markers by both inhibiting cell-cycle progression and cooperating with MyoD to promote the transcriptional activation activity of MEF2.

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BG Novitch, DB Spicer, PS Kim, WL Cheung and AB Lassar, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

Present address for BG Novitch: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA.

Present address for DB Spicer: Center for Molecular Medicine, Maine Medical Center Research Institute, 125 John Roberts Road, South Portland, Maine 04106, USA.

B.G.N. and D.B.S. contributed equally to this work.

E-mail address for AB Lassar (corresponding author): [email protected].