Death by NF-κB

Science's STKE  25 Apr 2000:
Vol. 2000, Issue 29, pp. tw3
DOI: 10.1126/stke.2000.29.tw3

Protein p53 is a tumor suppressor that acts by arresting the cell cycle and inducing apoptosis. Ryan et al. show that NF-κB activity can be anti-apoptotic or pro-apoptotic depending on the stimulus. Stimulation of NF-κB was essential in mediating p53-induced cell death, but stimulation of NF-κB was important for inhibiting cell death induced by tumor necrosis factor-α (TNF-α). The data suggest that p53 regulates NF-κB by mechanisms distinct from that activated by TNF. p53 activates NF-κB by stimulating the mitogen-activated protein kinase, MEK1, which phosphorylates and activates pp90rsk, which could then phosphorylate and inactivate IκB leading to NF-κB activation. Thus, one possible explanation for the divergent roles of NF-κB in the programmed cell death pathways activated by p53 and TNF-α may be the different mechanisms of activation of NF-κB. These dual roles for NF-κB have important implications for targeting NF-κB by chemotherapeutic agents to treat cancer: Inhibiting NF-κB in tumors with normal p53 function may actually decrease therapeutic effectiveness, whereas inhibiting NF-κB in cells with mutated p53 may increase therapeutic effectiveness.

Ryan, K.M., Ernst, M.K., Rice, N.R., and Vousden, K.H. (2000) Role of NF-κB in p53-mediated programmed cell death. Nature 404: 892-897. [Online Journal]