ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappa B through a common MEK extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage

作者：Panta GR; Kaur S; Cavin LG; Cortes ML; Mercurio F; Lothstein L; Sweatman TW; Israel M; Arsura M^*

来源：Molecular and Cellular Biology, 2004, 24(5): 1823-1835.

DOI：10.1128/MCB.24.5.1823-1835.2004

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.

• 出版日期2004-3