NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events
| Autor: | T T, Huang, S M, Wuerzberger-Davis, B J, Seufzer, S D, Shumway, T, Kurama, D A, Boothman, S, Miyamoto |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Cell Nucleus
DNA Replication Cytoplasm Proteasome Endopeptidase Complex Base Sequence NF-kappa B Apoptosis S Phase DNA-Binding Proteins Cysteine Endopeptidases NF-KappaB Inhibitor alpha Multienzyme Complexes Humans Camptothecin I-kappa B Proteins Topotecan Ubiquitins DNA Damage DNA Primers HeLa Cells Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 275(13) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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