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Molecular and Cellular Biology, August 2001, p. 4929-4937, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.4929-4937.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

c-Myc Is Necessary for DNA Damage-Induced Apoptosis in the G2 Phase of the Cell Cycle

Susumu Adachi,dagger Alvaro J. Obaya,Dagger Zhiyong Han, Noemi Ramos-Desimone, James H. Wyche, and John M. Sedivy*

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912

Received 13 February 2001/Returned for modification 10 April 2001/Accepted 28 April 2001

The c-myc proto-oncogene encodes a transcription factor that participates in the regulation of cellular proliferation, differentiation, and apoptosis. Ectopic overexpression of c-Myc has been shown to sensitize cells to apoptosis. We report here that cells lacking c-Myc activity due to disruption of the c-myc gene by targeted homologous recombination are defective in DNA damage-initiated apoptosis in the G2 phase of the cell cycle. The downstream effector of c-Myc is cyclin A, whose ectopic expression in c-myc-/- cells rescues the apoptosis defect. The kinetics of the G2 response indicate that the induction of cyclin A and the concomitant activation of Cdk2 represent an early step during commitment to apoptosis. In contrast, expression of cyclins E and D1 does not rescue the apoptosis defect, and apoptotic processes in G1 phase are not affected in c-myc-/- cells. These observations link DNA damage-induced apoptosis with cell cycle progression and implicate c-Myc in the functioning of a subset of these pathways.

* Corresponding author. Mailing address: Department of Molecular Biology, Cell Biology, and Biochemistry, Box G-J223, Brown University, Providence, RI 02912. Phone: (401) 863-9654. Fax: (401) 863-9653. E-mail: john_sedivy{at}brown.edu.

dagger Present address: Second Department of Medicine, Tokyo Medical and Dental University, Tokyo 113, Japan.

Dagger Present address: Area de Fisiologia, Facultad de Medicina, Universidad de Oviedo, Oviedo 33006, Spain.

Molecular and Cellular Biology, August 2001, p. 4929-4937, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.4929-4937.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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