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Molecular and Cellular Biology, May 2007, p. 3511-3520, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01448-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Interaction of a Cyclin E Fragment with Ku70 Regulates Bax-Mediated Apoptosis{triangledown} ,{dagger}

Suparna Mazumder,1 Dragos Plesca,1,3 Michael Kinter,4 and Alexandru Almasan1,2*

Departments of Cancer Biology,1 Cell Biology, The Lerner Research Institute,4 Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio 44195,2 School of Biomedical Sciences, Kent State University, Kent, Ohio 442403

Received 4 August 2006/ Returned for modification 1 September 2006/ Accepted 13 February 2007

The cyclin E/Cdk2 complex plays an essential role in the G1/S cell cycle transition and DNA replication. Earlier we showed that in hematopoietic tumor cells, caspase-mediated cleavage of cyclin E generates p18-cyclin E, which is unable to interact with Cdk2 and therefore plays a role independent of the cell cycle. The expression of a cleavage-resistant cyclin E mutant greatly diminishes apoptosis, indicating the critical role of cyclin E cleavage. p18-cyclin E expression can induce apoptosis or sensitization to apoptotic stimuli in many cell types. Here we identify Ku70 as a specific p18-cyclin E-interacting partner. In hematopoietic tumor cell lines, the association of p18-cyclin E with Ku70 induces the dissociation of Bax from Ku70, followed by Bax activation. This mechanism of Bax activation leads to the amplification of the apoptosis signal in all tumor cell lines examined. N-terminal Ku70 deletion mutants are unable to bind to p18-cyclin E to regulate its apoptotic effect. p18-cyclin E-mediated amplification of apoptosis is dependent on Bax and Ku70 being greatly diminished in Ku70–/– and Bax–/– mouse embryo fibroblasts and in hematopoietic cells where Bax knockdown was achieved by short interfering RNA. The p18-cyclin E/Ku70 and Bax/Ku70 interactions provide a balance between apoptosis and the survival of cells exposed to genotoxic stress.

* Corresponding author. Mailing address: Cleveland Clinic, Department of Cancer Biology, Cleveland, OH 44195. Phone: (216) 444-9970. Fax: (216) 445-6269. E-mail: almasaa{at}ccf.org

{triangledown} Published ahead of print on 26 February 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2007, p. 3511-3520, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01448-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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