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

Mol Cell Biol. 2004 Mar;24(5):1823-35. doi: 10.1128/MCB.24.5.1823-1835.2004.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / metabolism
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cell Survival
  • DNA Damage*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • I-kappa B Kinase
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • NF-kappa B / metabolism*
  • NIH 3T3 Cells
  • Nuclear Proteins
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Subunits / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction / physiology*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins

Substances

  • Antibiotics, Antineoplastic
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • NF-kappa B
  • Nuclear Proteins
  • Protein Subunits
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Doxorubicin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Mitogen-Activated Protein Kinase Kinases