Abstract
The Rel/NF-κB transcription factors play a key role in the regulation of apoptosis and in tumorigenesis by controlling the expressions of specific genes. To determine the role of the constitutive activity of RelA in tumorigenesis, we generated pancreatic tumor cell lines that express a dominant negative mutant of IκBα (IκBαM). In this report, we show that the inhibition of constitutive NF-κB activity, either by ectopic expression of IκBαM or by treating the cells with a proteasome inhibitor PS-341 which blocks intracellular degradation of IκBα proteins, downregulates the expression of bcl-xl. We identified two putative NF-κB binding sites (κB/A and B) in the bcl-xl promoter and found that these two sites interact with different NF-κB proteins. p65/p50 heterodimer interacts with κB/A site whereas p50/p50 homodimer interacts with κB/B. The bcl-xl promoter reporter gene assays reveal that NF-κB dependent transcriptional activation is mainly mediated by κB/A site, indicating that bcl-xl is one of the downstream target genes regulated by RelA/p50. Both IκBαM and PS-341 completely abolish NF-κB DNA binding activity; however, PS-341, but not ectopic expression of IκBαM, sensitized cells to apoptosis induced by Taxol. This is due to the Taxol-mediated reactivation of RelA through phosphorylation and degradation of IκBβ and the re-expression of NF-κB regulated bcl-xl gene in these cancer cells as ectopic expression of the bcl-xl gene confers resistance to Taxol-induced apoptosis in PS-341 sensitized cells. These results demonstrate the important function of various NF-κB/IκB complexes in regulating anti-apoptotic genes in response to apoptotic stimuli, and they raise the possibility that NF-κB : IκBα and NF-κB : IκBβ complexes are regulated by different upstream activators, and that NF-κB plays a key role in pancreatic tumorigenesis.
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Acknowledgements
We are grateful to Dr Inder M Verma for generously providing the IKK+/+, IKK1/α−/− and IKK2/β−/− MEF cells, Dr David McConkey for kindly providing PS-341. We also thank Carol Kohn and Pat Thomas for editorial assistance. This work was supported by grants from National Cancer Institute CA73675, CA78778, CA75517, the Lockton Fund for Pancreatic Cancer Research and Institution Research Grant from M.D. Anderson Cancer Center.
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Dong, Q., Sclabas, G., Fujioka, S. et al. The function of multiple IκB : NF-κB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene 21, 6510–6519 (2002). https://doi.org/10.1038/sj.onc.1205848
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DOI: https://doi.org/10.1038/sj.onc.1205848
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