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Published online 1 November 2004. doi:10.1083/jcb.200408164
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 3, 417-423
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 A pRb-independent mechanism preserves the postmitotic state in terminally differentiated skeletal muscle cells

Grazia Camarda1, Francesca Siepi1, Deborah Pajalunga1, Camilla Bernardini1, Rossella Rossi2, Alessandra Montecucco2, Ettore Meccia1, and Marco Crescenzi1

1 Department of Environment and Primary Prevention, Higher Institute of Health, 00161 Roma, Italy
2 Istituto di Genetica Molecolare CNR, 27100 Pavia, Italy

Correspondence to Marco Crescenzi: crescenz{at}iss.it


Abstract
In skeletal muscle differentiation, the retinoblastoma protein (pRb) is absolutely necessary to establish definitive mitotic arrest. It is widely assumed that pRb is equally essential to sustain the postmitotic state, but this contention has never been tested. Here, we show that terminal proliferation arrest is maintained in skeletal muscle cells by a pRb-independent mechanism.

Acute Rb excision from conditional knockout myotubes caused reexpression of E2F transcriptional activity, cyclin-E and -A kinase activities, PCNA, DNA ligase I, RPA, and MCM2, but did not induce DNA synthesis, showing that pRb is not indispensable to preserve the postmitotic state of these cells. Muscle-specific gene expression was significantly down-regulated, showing that pRb is constantly required for optimal implementation of the muscle differentiation program. Rb-deleted myotubes were efficiently reactivated by forced expression of cyclin D1 and Cdk4, indicating a functionally significant target other than pRb for these molecules. Finally, Rb removal induced no DNA synthesis even in pocket-protein null cells. Thus, the postmitotic state of myotubes is maintained by at least two mechanisms, one of which is pocket-protein independent.

G. Camarda and F. Siepi contributed equally to this work.

Abbreviations used in this paper: AdCre, Cre recombinase-carrying adenovirus; {Delta}Rb, Rb-deleted; {Delta}Rb-Mt, {Delta}Rb myotubes; IF, immunofluorescence; KO, knockout; MEF, mouse embryo fibroblasts; m.o.i., multiplicity of infection; MSC, muscle satellite cell; MyHC, myosin heavy chain; pRb, retinoblastoma protein; TD, terminally differentiated.


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