ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-κB through a Common MEK/Extracellular Signal-Regulated Kinase/p90 rsk Signaling Pathway in Response to Distinct Forms of DNA Damage

Ganesh R. Panta, Swayamjot Kaur, Lakita G. Cavin, Maria L. Cortés, Frank Mercurio, Leonard Lothstein, Trevor W. Sweatman, Mervyn Israel, Marcello Arsura

Research output: Contribution to journalArticle

105 Citations (Scopus)

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 κB (NF-κB) 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)/p90rsk signaling cascade in a p53-independent fashion. In turn, p90rsk interacts with the IκB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-κB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-κB pathway that opposes the apoptotic response following DNA damage.

Original languageEnglish (US)
Pages (from-to)1823-1835
Number of pages13
JournalMolecular and cellular biology
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2004

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90-kDa Ribosomal Protein S6 Kinases
DNA-Activated Protein Kinase
Catalytic DNA
Ataxia Telangiectasia
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
DNA Damage
Catalytic Domain
Mitogen-Activated Protein Kinases
I-kappa B Kinase
Anthracyclines
Phosphatidylinositols
Doxorubicin
Cell Survival
Phosphotransferases
N-benzyladriamycin

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-κB through a Common MEK/Extracellular Signal-Regulated Kinase/p90 rsk Signaling Pathway in Response to Distinct Forms of DNA Damage. / Panta, Ganesh R.; Kaur, Swayamjot; Cavin, Lakita G.; Cortés, Maria L.; Mercurio, Frank; Lothstein, Leonard; Sweatman, Trevor W.; Israel, Mervyn; Arsura, Marcello.

In: Molecular and cellular biology, Vol. 24, No. 5, 01.03.2004, p. 1823-1835.

Research output: Contribution to journalArticle

Panta, Ganesh R. ; Kaur, Swayamjot ; Cavin, Lakita G. ; Cortés, Maria L. ; Mercurio, Frank ; Lothstein, Leonard ; Sweatman, Trevor W. ; Israel, Mervyn ; Arsura, Marcello. / ATM and the Catalytic Subunit of DNA-Dependent Protein Kinase Activate NF-κB through a Common MEK/Extracellular Signal-Regulated Kinase/p90 rsk Signaling Pathway in Response to Distinct Forms of DNA Damage. In: Molecular and cellular biology. 2004 ; Vol. 24, No. 5. pp. 1823-1835.
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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 κB (NF-κB) 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)/p90rsk signaling cascade in a p53-independent fashion. In turn, p90rsk interacts with the IκB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-κB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-κB pathway that opposes the apoptotic response following DNA damage.",
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AU - Kaur, Swayamjot

AU - Cavin, Lakita G.

AU - Cortés, Maria L.

AU - Mercurio, Frank

AU - Lothstein, Leonard

AU - Sweatman, Trevor W.

AU - Israel, Mervyn

AU - Arsura, Marcello

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N2 - We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor κB (NF-κB) 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)/p90rsk signaling cascade in a p53-independent fashion. In turn, p90rsk interacts with the IκB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-κB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-κB pathway that opposes the apoptotic response following DNA damage.

AB - We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor κB (NF-κB) 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)/p90rsk signaling cascade in a p53-independent fashion. In turn, p90rsk interacts with the IκB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-κB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-κB pathway that opposes the apoptotic response following DNA damage.

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