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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.

N uclear factor B (NF-B) was first identified as a nuclear factor specific to B cells bound to the B site of the light chain gene enhancer. 1 Classic NF-B, which is composed of an NF-B1 (p50) and RelA (p65) subunit, belongs to a family of dimeric transcription factors typified by an amino terminal stretch of approximately 300 amino acids, named the Rel homology domain, involved in DNA binding and dimerization of the various subunits. 2 In resting non-B cells, NF-B is sequestered in the cytoplasm through association with a family of inhibitory molecules, of which inhibitor B (IB)-␣ is the best characterized. In response to proinflammatory cytokines, growth factors, or genotoxic stress, inducible phosphorylation of IB-␣ involves the IB kinase (IKK) complex, which is formed by the IKK-␣ and IKK-␤ catalytic subunits and by a scaffold subunit termed IKK-␥/NEMO. 3 Following phosphorylation by IKKs, IB-␣ is degraded through the proteasome pathway, thereby promoting nuclear translocation of NF-B, which then regulates genes involved in immune response, cell adhesion, cell cycle, transformation, and cell survival. 4 In addition, IB-␣ can be phosphorylated at the C-terminal PEST sequence of IB-␣ by the protein kinase CK2 (formerly casein kinase II). 5-8 CK2 is a ubiquitous tetrameric serine-threonine kinase composed of 2 ␣ and ␣Ј catalytic subunits of 43 and 38 kd, respectively, and 2 regulatory ␤ subunits. 9 CK2 has been implicated in the regulation of cell growth and survival of normal and neoAbbreviations: NF-B, nuclear factor B; IB, inhibitor B; IKK, inhibitor B kinase;

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