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The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis.

Publication ,  Journal Article
Dong, QG; Sclabas, GM; Fujioka, S; Schmidt, C; Peng, B; Wu, T; Tsao, M-S; Evans, DB; Abbruzzese, JL; McDonnell, TJ; Chiao, PJ
Published in: Oncogene
September 19, 2002

The Rel/NF-kappaB 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 IkappaBalpha (IkappaBalphaM). In this report, we show that the inhibition of constitutive NF-kappaB activity, either by ectopic expression of IkappaBalphaM or by treating the cells with a proteasome inhibitor PS-341 which blocks intracellular degradation of IkappaBalpha proteins, downregulates the expression of bcl-xl. We identified two putative NF-kappaB binding sites (kappaB/A and B) in the bcl-xl promoter and found that these two sites interact with different NF-kappaB proteins. p65/p50 heterodimer interacts with kappaB/A site whereas p50/p50 homodimer interacts with kappaB/B. The bcl-xl promoter reporter gene assays reveal that NF-kappaB dependent transcriptional activation is mainly mediated by kappaB/A site, indicating that bcl-xl is one of the downstream target genes regulated by RelA/p50. Both IkappaBalphaM and PS-341 completely abolish NF-kappaB DNA binding activity; however, PS-341, but not ectopic expression of IkappaBalphaM, sensitized cells to apoptosis induced by Taxol. This is due to the Taxol-mediated reactivation of RelA through phosphorylation and degradation of IkappaBbeta and the re-expression of NF-kappaB 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-kappaB/IkappaB complexes in regulating anti-apoptotic genes in response to apoptotic stimuli, and they raise the possibility that NF-kappaB : IkappaBalpha and NF-kappaB : IkappaBbeta complexes are regulated by different upstream activators, and that NF-kappaB plays a key role in pancreatic tumorigenesis.

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Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

September 19, 2002

Volume

21

Issue

42

Start / End Page

6510 / 6519

Location

England

Related Subject Headings

  • bcl-X Protein
  • Up-Regulation
  • Tumor Cells, Cultured
  • Transcriptional Activation
  • Pyrophosphatases
  • Pyrazines
  • Proto-Oncogene Proteins c-bcl-2
  • Protease Inhibitors
  • Promoter Regions, Genetic
  • Pancreatic Neoplasms
 

Citation

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Dong, Q. G., Sclabas, G. M., Fujioka, S., Schmidt, C., Peng, B., Wu, T., … Chiao, P. J. (2002). The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene, 21(42), 6510–6519. https://doi.org/10.1038/sj.onc.1205848
Dong, Qiang G., Guido M. Sclabas, Shuichi Fujioka, Christian Schmidt, Bailu Peng, TianAi Wu, Ming-Sound Tsao, et al. “The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis.Oncogene 21, no. 42 (September 19, 2002): 6510–19. https://doi.org/10.1038/sj.onc.1205848.
Dong QG, Sclabas GM, Fujioka S, Schmidt C, Peng B, Wu T, et al. The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene. 2002 Sep 19;21(42):6510–9.
Dong, Qiang G., et al. “The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis.Oncogene, vol. 21, no. 42, Sept. 2002, pp. 6510–19. Pubmed, doi:10.1038/sj.onc.1205848.
Dong QG, Sclabas GM, Fujioka S, Schmidt C, Peng B, Wu T, Tsao M-S, Evans DB, Abbruzzese JL, McDonnell TJ, Chiao PJ. The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene. 2002 Sep 19;21(42):6510–6519.

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

September 19, 2002

Volume

21

Issue

42

Start / End Page

6510 / 6519

Location

England

Related Subject Headings

  • bcl-X Protein
  • Up-Regulation
  • Tumor Cells, Cultured
  • Transcriptional Activation
  • Pyrophosphatases
  • Pyrazines
  • Proto-Oncogene Proteins c-bcl-2
  • Protease Inhibitors
  • Promoter Regions, Genetic
  • Pancreatic Neoplasms