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
Copyright policy )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
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.
- Harvard Medical School United States
- Massachusetts General Hospital United States
- Celgene United States
- University of Tennessee at Knoxville United States
- Harvard University United States
Mitogen-Activated Protein Kinase Kinases, Antibiotics, Antineoplastic, Cell Survival, NF-kappa B, Nuclear Proteins, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, DNA-Activated Protein Kinase, Fibroblasts, Protein Serine-Threonine Kinases, I-kappa B Kinase, DNA-Binding Proteins, Enzyme Activation, Mice, Doxorubicin, NIH 3T3 Cells, Animals, Humans, Enzyme Inhibitors, DNA Damage
Mitogen-Activated Protein Kinase Kinases, Antibiotics, Antineoplastic, Cell Survival, NF-kappa B, Nuclear Proteins, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, DNA-Activated Protein Kinase, Fibroblasts, Protein Serine-Threonine Kinases, I-kappa B Kinase, DNA-Binding Proteins, Enzyme Activation, Mice, Doxorubicin, NIH 3T3 Cells, Animals, Humans, Enzyme Inhibitors, DNA Damage
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