NF-κB activation by camptothecin. A linkage between nuclear dna damage and cytoplasmic signaling events

Tony T. Huang, Shelly M. Wuerzberger-Davis, Bradley J. Seufzer, Stuart D. Shumway, Takeshi Kurama, David A. Boothman, Shigeki Miyamoto

Research output: Contribution to journalArticle

146 Scopus citations

Abstract

Activation of the transcription factor NF-κB by extracellular signals involves its release from the inhibitor protein IκBα in the cytoplasm and subsequent nuclear translocation. NF-κB 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-κB by a mechanism that is dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. NF-κB 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-κB involves degradation of cytoplasmic IκBα by the ubiquitin-proteasome pathway in a manner that depends on the IκB kinase complex. Finally, inhibition of NF-κB 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 IκBα and nuclear translocation of NF- κB to attenuate the apoptotic response.

Original languageEnglish (US)
Pages (from-to)9501-9509
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number13
DOIs
StatePublished - Mar 31 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Huang, T. T., Wuerzberger-Davis, S. M., Seufzer, B. J., Shumway, S. D., Kurama, T., Boothman, D. A., & Miyamoto, S. (2000). NF-κB activation by camptothecin. A linkage between nuclear dna damage and cytoplasmic signaling events. Journal of Biological Chemistry, 275(13), 9501-9509. https://doi.org/10.1074/jbc.275.13.9501