NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events

Activation of the transcription factor NF-kappaB by extracellular signals involves its release from the inhibitor protein IkappaBalpha in the cytoplasm and subsequent nuclear translocation. NF-kappaB can also be activated by the anticancer agent camptothecin (CPT), which inhibits DNA topoisomerase (...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-03, Vol.275 (13), p.9501
Main Authors: Huang, T T, Wuerzberger-Davis, S M, Seufzer, B J, Shumway, S D, Kurama, T, Boothman, D A, Miyamoto, S
Format: Article
Language:English
Subjects:
Apoptosis
Base Sequence
Camptothecin - pharmacology
Cell Nucleus - drug effects
Cell Nucleus - metabolism
Cysteine Endopeptidases - metabolism
Cytoplasm - drug effects
Cytoplasm - metabolism
DNA Damage
DNA Primers
DNA Replication - drug effects
DNA-Binding Proteins - metabolism
HeLa Cells
Humans
I-kappa B Proteins
Multienzyme Complexes - metabolism
NF-kappa B - antagonists & inhibitors
NF-kappa B - metabolism
NF-KappaB Inhibitor alpha
Proteasome Endopeptidase Complex
S Phase - drug effects
Signal Transduction - drug effects
Topotecan - pharmacology
Ubiquitins - metabolism
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Summary:Activation of the transcription factor NF-kappaB by extracellular signals involves its release from the inhibitor protein IkappaBalpha in the cytoplasm and subsequent nuclear translocation. NF-kappaB can also be activated by the anticancer agent camptothecin (CPT), which inhibits DNA topoisomerase (Topo) I activity and causes DNA double-strand breaks during DNA replication to induce S phase-dependent cytotoxicity. Here we show that CPT activates NF-kappaB by a mechanism that is dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. NF-kappaB activation by CPT is dramatically diminished in cytoplasts and in CEM/C2 cells expressing a mutant Topo I protein that fails to bind CPT. This response is intensified in S phase cell populations and is prevented by the DNA polymerase inhibitor aphidicolin. In addition, CPT activation of NF-kappaB involves degradation of cytoplasmic IkappaBalpha by the ubiquitin-proteasome pathway in a manner that depends on the IkappaB kinase complex. Finally, inhibition of NF-kappaB activation augments CPT-induced apoptosis. These findings elucidate the progression of signaling events that initiates in the nucleus with CPT-Topo I interaction and continues in the cytoplasm resulting in degradation of IkappaBalpha and nuclear translocation of NF-kappaB to attenuate the apoptotic response.
ISSN:0021-9258