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Role of NF-κB in p53-mediated programmed cell death

Nature volume 404, pages 892–897 (2000)Cite this article

Abstract

The tumour suppressor p53 inhibits cell growth through activation of cell-cycle arrest and apoptosis1, and most cancers have either mutation within the p53 gene or defects in the ability to induce p53. Activation or re-introduction of p53 induces apoptosis in many tumour cells and may provide effective cancer therapy2. One of the key proteins that modulates the apoptotic response is NF-κB, a transcription factor that can protect or contribute to apoptosis3. Here we show that induction of p53 causes an activation of NF-κB that correlates with the ability of p53 to induce apoptosis. Inhibition or loss of NF-κB activity abrogated p53-induced apoptosis, indicating that NF-κB is essential in p53-mediated cell death. Activation of NF-κB by p53 was distinct from that mediated by tumour-necrosis factor-α and involved MEK1 and the activation of pp90rsk. Inhibition of MEK1 blocked activation of NF-κB by p53 and completely abrogated p53-induced cell death. We conclude that inhibition of NF-κB in tumours that retain wild-type p53 may diminish, rather than augment, a therapeutic response.

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Figure 1: DNA binding by NF-κB.
Figure 2: NF-κB activation is associated with the apoptotic activity of p53 and is not induced after cell death induced by Bax.
Figure 3: NF-κB is essential for p53-induced cell death.
Figure 4: Inhibition of NF-κB abrogates p53-mediated apoptosis, but not cell cycle arrest.
Figure 5: E1A transformed p65-/- MEFs are resistant to p53-mediated apoptosis.
Figure 6: Signalling pathways involved in the activation of NF-κB by p53 are distinct from those engaged by TNFα and involve the RAF/MAPK pathway.

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Acknowledgements

We are grateful to A. Phillips, M. Dobrovolskaia and D. Woods for helpful discussion. We thank C. Rosen, G. Nunez, A. Israel and E. Harlow for plasmids, and D. Baltimore for the p65-deficient MEFs. We are also indebted to S. Lowe for providing us with E1A-expressing retroviruses.

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Authors and Affiliations

  1. Regulation of Cell Growth Laboratory, NCI-FCRDC, Building 560, Room 22-96, West 7th Street, Frederick, 21702-1201, Maryland, USA

    Kevin M. Ryan, Mary K. Ernst, Nancy R. Rice & Karen H. Vousden

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Correspondence to Karen H. Vousden.

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Ryan, K., Ernst, M., Rice, N. et al. Role of NF-κB in p53-mediated programmed cell death. Nature 404, 892–897 (2000). https://doi.org/10.1038/35009130

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