Work

ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-κB through a Common MEK/Extracellular Signal-Regulated Kinase/p90rsk Signaling Pathway in Response to Distinct Forms of DNA Damage

Year: 2004

Type: article

Abstract: We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor kappaB (NF-kappaB) 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 IkappaB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-kappaB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-kappaB pathway that opposes the apoptotic response following DNA damage.

Source: Molecular and Cellular Biology

DOI: 10.1128/mcb.24.5.1823-1835.2004