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

Kevin M. Ryan, Mary K. Ernst, Nancy R. Rice and Karen H. Vousden ()
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Kevin M. Ryan: Regulation of Cell Growth Laboratory, NCI-FCRDC, Building 560, Room 22-96
Mary K. Ernst: Regulation of Cell Growth Laboratory, NCI-FCRDC, Building 560, Room 22-96
Nancy R. Rice: Regulation of Cell Growth Laboratory, NCI-FCRDC, Building 560, Room 22-96
Karen H. Vousden: Regulation of Cell Growth Laboratory, NCI-FCRDC, Building 560, Room 22-96

Nature, 2000, vol. 404, issue 6780, 892-897

Abstract: 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.

Date: 2000
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DOI: 10.1038/35009130

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