Abstract
Activation of the NF-κB transcription factors has been shown to be directly influenced by changes in the microtubule cytoskeleton network. To better understand cytoskeletal regulation of NF-κB, experiments were performed to determine whether the microtubule (MT) stabilizing agent taxol could modulate NF-κB activation in the presence of different NF-κB inducers. Pretreatment of murine NIH3T3 and human 293 cells with 5 μM taxol resulted in complete inhibition of phorbol, 12-myristate, 13-acetate (PMA) mediated NF-κB activation, detected as the loss of DNA binding and reduced NF-κB dependent reporter gene activity. Furthermore, in COS-7 and NIH3T3 cells, PMA-induced IκBα turnover was dramatically reduced in taxol treated cells, mediated via the inhibition of IκBα phosphorylation. However, taxol did not prevent TNF-α induced IκBα phosphorylation, degradation, or NF-κB activation, indicating that TNF-α acts through a microtubule-independent pathway. In vitro kinase assays with PMA stimulated cell extracts demonstrated that taxol reduced protein kinase C activity by 30%, thus implicating the loss of PKC activity as a possible regulatory target of taxol-mediated suppression of NF-κB. Since PMA causes modulation of cytoarchitecture through PKC activation, microtubule integrity and cell morphology was analysed by indirect immunofluorescence. Both PMA and nocodazole, a MT depolymerizing agent, caused microtubule depolymerization, whereas TNF-α did not alter MT integrity; concomitant taxol treatment blocked both nocodazole and PMA induced depolymerization of MTs, as well as NF-κB induction, thus demonstrating a link between microtubule depolymerization and NF-κB activation. These observations illustrate a novel biological activity of taxol as a selective inhibitor of NF-κB activity, suggesting a link between the state of microtubule integrity and gene regulation.
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Acknowledgements
The authors wish to thank Dr Moulay Aloui-Jamali for reagents and advice as well as members of the Molecular Oncology Group for helpful discussions. This research was supported by grants from the Medical Research Council of Canada and National Cancer Institute to JH. HK was supported by a studentship from FCAR, PC by a Post-doctoral Fellowship from FRSQ, RL by a Fraser Monat McPherson Fellowship from McGill University and JH by a MRC Senior Scientist award.
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Spencer, W., Kwon, H., Crépieux, P. et al. Taxol selectively blocks microtubule dependent NF-κB activation by phorbol ester via inhibition of IκBα phosphorylation and degradation. Oncogene 18, 495–505 (1999). https://doi.org/10.1038/sj.onc.1202335
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DOI: https://doi.org/10.1038/sj.onc.1202335
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