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Molecular and Cellular Biology, July 1999, p. 5203-5217, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Critical Role Played by Cyclin D3 in the MyoD-Mediated Arrest of Cell Cycle during Myoblast Differentiation

Carlo Cenciarelli,1,dagger Francesca De Santa,1 Pier Lorenzo Puri,2,Dagger Elisabetta Mattei,1 Letizia Ricci,1 Federica Bucci,1 Armando Felsani,1,* and Maurizia Caruso3,*

Istituto di Tecnologie Biomediche1 and Istituto di Biologia Cellulare,3 CNR, 00137 Rome, and Fondazione Andrea Cesalpino and Istituto I Clinica Medica, University of Roma "La Sapienza," 00161 Rome,2 Italy

Received 25 September 1998/Returned for modification 24 November 1998/Accepted 9 March 1999

During the terminal differentiation of skeletal myoblasts, the activities of myogenic factors regulate not only tissue-specific gene expressions but also the exit from the cell cycle. The induction of cell cycle inhibitors such as p21 and pRb has been shown to play a prominent role in the growth arrest of differentiating myoblasts. Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. In differentiated myocytes, cyclin D3 also becomes stabilized and is found nearly totally complexed with unphosphorylated pRb. The detection of complexes containing cyclin D3, cdk4, p21, and PCNA suggests that cdk4, along with PCNA, may get sequestered into high-order structures held together by pRb and cyclin D3. Cyclin D3 up-regulation and stabilization is inhibited by adenovirus E1A, and this correlates with the ability of E1A to promote pRb phosphorylation; conversely, the overexpression of cyclin D3 in differentiated myotubes counteracts the E1A-mediated reactivation of DNA synthesis. These results indicate that cyclin D3 critically contributes to the irreversible exit of differentiating myoblasts from the cell cycle.

* Corresponding author. Mailing address for Maurizia Caruso: Istituto Biologia Cellulare, viale Marx 43, 00137 Rome, Italy. Phone: (39 06) 86090294. Fax: (39 06) 8273287. E-mail: caruso{at}ibc.rm.cnr.it. Mailing address for Armando Felsani: Istituto Tecnologie Biomediche, viale Marx 43, 00137 Rome, Italy. Phone: (39 06) 86090500. Fax: (39 06) 86090325. E-mail: felsani{at}itbm.rm.cnr.it.

dagger Present address: Department of Pediatrics, New York University-Medical Center (Tisch Hospital), New York, NY 10016.

Dagger Present address: Department of Biology and the Cancer Center, University of California, San Diego, La Jolla, CA 92093-0322.

Molecular and Cellular Biology, July 1999, p. 5203-5217, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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