Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle

L. Latella, A. Sacco, D. Pajalunga, M. Tiainen, D. Macera, M. D'Angelo, A. Felici, A. Sacchi, M. Crescenzi

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

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-G, 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.

Original languageEnglish
Pages (from-to)5631-5643
Number of pages13
JournalMolecular and Cellular Biology
Volume21
Issue number16
DOIs
Publication statusPublished - 2001

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Cyclin D1
Skeletal Muscle Fibers
Cell Cycle
Phosphotransferases
Cyclin E
Myoblasts
Cell Cycle Checkpoints
Adipocytes
Muscle Cells
Cell Differentiation
Mammals
Skeletal Muscle
Maintenance
Phosphorylation
Gene Expression
Neurons
Muscles
DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle. / Latella, L.; Sacco, A.; Pajalunga, D.; Tiainen, M.; Macera, D.; D'Angelo, M.; Felici, A.; Sacchi, A.; Crescenzi, M.

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

Research output: Contribution to journalArticle

Latella, L, Sacco, A, Pajalunga, D, Tiainen, M, Macera, D, D'Angelo, M, Felici, A, Sacchi, A & Crescenzi, M 2001, 'Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle', Molecular and Cellular Biology, vol. 21, no. 16, pp. 5631-5643. https://doi.org/10.1128/MCB.21.16.5631-5643.2001
Latella, L. ; Sacco, A. ; Pajalunga, D. ; Tiainen, M. ; Macera, D. ; D'Angelo, M. ; Felici, A. ; Sacchi, A. ; Crescenzi, M. / Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle. In: Molecular and Cellular Biology. 2001 ; Vol. 21, No. 16. pp. 5631-5643.
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