p53 induces NF-κB activation by an IκB kinase-independent mechanism involving phosphorylation of p65 by ribosomal S6 kinase 1

Apoptosis induced by p53 has been proposed to involve activation of the transcription factor NF-κB. Here we describe the novel molecular mechanism through which p53 and DNA-damaging agents activate NF-κB. NF-κB induction by p53 does not occur through classical activation of the IκB kinases and degradation of IκBα. Rather, p53 expression stimulates the serine/threonine kinase ribosomal S6 kinase 1 (RSK1), which in turn phosphorylates the p65 subunit of NF-κB. The lower affinity of RSK1-phosphorylated p65 for its negative regulator, IκBα, decreases IκBα-mediated nuclear export of shuttling forms of NF-κB, thereby promoting the binding and action of NF-κB on cognate κB enhancers. These findings highlight a rather unusual pathway of NF-κB activation, which is utilized by the p53 tumor suppressor.