Abstract
In chronic myelogenous leukemia (CML), the oncogene bcr-abl encodes a dysregulated tyrosine kinase that inhibits apoptosis. We showed previously that human erythroleukemia K562 cells are resistant to antineoplastic drug (taxol)-induced apoptosis through the atypical protein kinase C iota isozyme (PKCι), a kinase downstream of Bcr-Abl. The mechanism(s) by which PKCι mediates cell survival to taxol is unknown. Here we demonstrate that PKCι requires the transcription factor nuclear factor-κB (NF-κB) to confer cell survival. At apoptosis-inducing concentrations, taxol weakly induces IκBα proteolysis and NF-κB translocation in K562 cells, but potently induces its transcriptional activity. Inhibition of NF-κB activity (by blocking IκBα degradation) significantly sensitizes cells to taxol-induced apoptosis. Likewise, K562 cells expressing antisense PKCι mRNA or kinase dead PKCι (PKCι-KD) are sensitized to taxol; these cells are rescued from apoptosis by NF-κB overexpression. Expression of constitutively active PKCι (PKCι-CA) upregulates NF-κB transactivation and rescues cells from apoptosis in the absence of Bcr-Abl tyrosine kinase activity. Using a chimeric GAL4-RelA transactivator, we find that taxol potently activates GAL4-RelA-dependent transcription. This activation was further upregulated by expression of PKCι-CA and inhibited by expression of PKCι-KD. Our results indicate that RelA transactivation is an important downstream target of the PKCι-mediated Bcr-Abl signaling pathway and is required for resistance to taxol-induced apoptosis.
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Acknowledgements
This work was supported in part by grant CA56869 (to AP Fields), AI40218 (to AR Brasier), and NIEHS ES06676 (to RS Lloyd, UTMB). AP Fields is a scholar of the Leukemia Lymphoma Society (formerly the Leukemia Society of America).
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Lu, Y., Jamieson, L., Brasier, A. et al. NF-κB/RelA transactivation is required for atypical protein kinase Cι-mediated cell survival. Oncogene 20, 4777–4792 (2001). https://doi.org/10.1038/sj.onc.1204607
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DOI: https://doi.org/10.1038/sj.onc.1204607
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