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Molecular and Cellular Biology, April 2004, p. 2968-2977, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2968-2977.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Apoptosis Associated with Deregulated E2F Activity Is Dependent on E2F1 and Atm/Nbs1/Chk2

Harry A. Rogoff,1 Mary T. Pickering,2 Fiona M. Frame,2 Michelle E. Debatis,2 Yolanda Sanchez,3 Stephen Jones,4 and Timothy F. Kowalik1,2*

Program in Immunology and Virology,1 Department of Molecular Genetics and Microbiology,2 Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655,4 Department of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 452213

Received 4 September 2003/ Returned for modification 7 October 2003/ Accepted 2 January 2004

The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis and is critical for normal development and cancer prevention. Here we define a transcription-mediated pathway in which deregulation of E2F1 by ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16 signals apoptosis by inducing the expression of Chk2, a component of the DNA damage response. E2F1- and E7-mediated apoptosis are compromised in cells from patients with the related disorders ataxia telangiectasia and Nijmegen breakage syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm and Nbs1 contribute to Chk2 activation and p53 phosphorylation following deregulation of normal Rb growth control. E2F2, a related E2F family member that does not induce apoptosis, also activates Atm, resulting in phosphorylation of p53. However, we found that the key commitment step in apoptosis induction is the ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest that E2F1 plays a central role in signaling disturbances in the Rb growth control pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655. Phone: (508) 856-6035. Fax: (508) 856-5920. E-mail: timothy.kowalik{at}umassmed.edu.

Molecular and Cellular Biology, April 2004, p. 2968-2977, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2968-2977.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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