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

2004; Taylor & Francis; Volume: 24; Issue: 5 Linguagem: Inglês

10.1128/mcb.24.5.1823-1835.2004

1098-5549

Ganesh R. Panta, Swayamjot Kaur, Lakita G. Cavin, Maria L. Cortés, Frank Mercurio, Leonard Lothstein, Trevor W. Sweatman, Mervyn Israel, Marcello Arsura,

DNA Repair Mechanisms

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 p53independent 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.