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

• Published in: Nature (London) 2000-04, Vol.404 (6780), p.892-897
• Main Authors: Vousden, Karen H, Ryan, Kevin M, Ernst, Mary K, Rice, Nancy R
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; letter; MEK1 protein; Molecular and cellular biology; multidisciplinary; NF-^KB protein; NF-B protein; p53 protein; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35009130

The tumour suppressor p53 inhibits cell growth through activation of cell-cycle arrest and apoptosis, 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 therapy. One of the key proteins that modulates the apoptotic response is NF-κB, a transcription factor that can protect or contribute to apoptosis. 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.