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Molecular and Cellular Biology, August 2001, p. 5631-5643, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5631-5643.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Reconstitution of Cyclin D1-Associated Kinase Activity Drives Terminally Differentiated Cells into the Cell Cycle

Lucia Latella,1,dagger Alessandra Sacco,1 Deborah Pajalunga,1 Marianne Tiainen,2,Dagger Daniela Macera,2 Marco D'Angelo,2 Angelina Felici,3,§ Ada Sacchi,2 and Marco Crescenzi1,*

Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá,1 Laboratory of Molecular Oncogenesis, Regina Elena Cancer Institute,2 and Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata,3 Rome, Italy

Received 11 January 2001/Returned for modification 13 February 2001/Accepted 23 May 2001

Terminal cell differentiation entails definitive withdrawal from the cell cycle. Although most of the cells of an adult mammal are terminally differentiated, the molecular mechanisms preserving the postmitotic state are insufficiently understood. Terminally differentiated skeletal muscle cells, or myotubes, are a prototypic terminally differentiated system. We previously identified a mid-G1 block preventing myotubes from progressing beyond this point in the cell cycle. In this work, we set out to define the molecular basis of such a block. It is shown here that overexpression of highly active cyclin E and cdk2 in myotubes induces phosphorylation of pRb but cannot reactivate DNA synthesis, underscoring the tightness of cell cycle control in postmitotic cells. In contrast, forced expression of cyclin D1 and wild-type or dominant-negative cdk4 in myotubes restores physiological levels of cdk4 kinase activity, allowing progression through the cell cycle. Such reactivation occurs in myotubes derived from primary, as well as established, C2C12 myoblasts and is accompanied by impairment of muscle-specific gene expression. Other terminally differentiated systems as diverse as adipocytes and nerve cells are similarly reactivated. Thus, the present results indicate that the suppression of cyclin D1-associated kinase activity is of crucial importance for the maintenance of the postmitotic state in widely divergent terminally differentiated cell types.

* Corresponding author. Mailing address: Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39 0649903163. Fax: 39 0649902355. E-mail: crescenz{at}iss.it.

dagger Present address: Institute of Cancer Biology, Danish Cancer Society, 2100 Copenhagen, Denmark.

Dagger Present address: Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.

§ Present address: Laboratory of Cellular and Molecular Biology, NCI, NIH, Bethesda, MD 20892.

Molecular and Cellular Biology, August 2001, p. 5631-5643, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5631-5643.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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