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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibiotics, Antineoplastic / chemistry
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Antibiotics, Antineoplastic / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins
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Cell Survival
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DNA Damage*
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DNA-Activated Protein Kinase
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DNA-Binding Proteins*
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Doxorubicin / analogs & derivatives
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Doxorubicin / metabolism
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Enzyme Activation
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Enzyme Inhibitors / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Humans
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I-kappa B Kinase
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Mice
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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NF-kappa B / metabolism*
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NIH 3T3 Cells
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Nuclear Proteins
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Protein Serine-Threonine Kinases / metabolism*
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Protein Subunits / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Signal Transduction / physiology*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
Substances
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Antibiotics, Antineoplastic
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Cell Cycle Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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NF-kappa B
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Nuclear Proteins
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Protein Subunits
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Doxorubicin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases, 90-kDa
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Mitogen-Activated Protein Kinase Kinases