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Molecular and Cellular Biology, March 2004, p. 1823-1835, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1823-1835.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-B through a Common MEK/Extracellular Signal-Regulated Kinase/p90^rsk Signaling Pathway in Response to Distinct Forms of DNA Damage

Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, College of Medicine, Memphis, Tennessee 38163,¹ Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129,² Celgene Signal Research Division, San Diego, California 92121³

Received 2 July 2003/ Returned for modification 21 August 2003/ Accepted 2 December 2003

We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor B (NF-B) activation and chemoresistance in response to DNA damage. We show that the anthracycline doxorubicin (DOX) and its congener N-benzyladriamycin (AD 288) selectively activate ATM and DNA-PK, respectively. Both ATM and DNA-PK promote sequential activation of the mitogen-activated protein kinase (MAPK)/p90^rsk signaling cascade in a p53-independent fashion. In turn, p90^rsk interacts with the IB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-B activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-B pathway that opposes the apoptotic response following DNA damage.

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