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Molecular and Cellular Biology, August 2001, p. 5631-5643, Vol. 21, No. 16
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.
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


*
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.
Present address: Institute of Cancer Biology, Danish Cancer
Society, 2100 Copenhagen, Denmark.
Present address: Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
§
Present address: Laboratory of Cellular and Molecular Biology, NCI,
NIH, Bethesda, MD 20892.
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