p53 Induces NF-κB Activation by an IκB Kinase-independent Mechanism Involving Phosphorylation of p65 by Ribosomal S6 Kinase 1

Abstract

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

Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

“…p53 activation did not affect the downstream targets Bax or p21, which might contribute to either enhancement of apoptosis or cell cycle arrest (data not shown). As it has been shown previously that upon treatment with chemotherapeutic drugs, NF-kB can be activated in a p53-dependent manner through activation of the ribosomal S6 kinase 2 independent of the IKK pathway (Bohuslav et al, 2004), we assume that p53 activation in our system also accounts for the late IL-1-independent NF-kB activation. In accordance with this, Ryan et al reported that p53-mediated NF-kB activation upon doxorubicin treatment is mediated by the MAP kinase MEK1 and activation of the 90-kDa ribosomal S6 kinase pp90 rsk .…”

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…91 Activation of NF-kB by DNA damage can occur through multiple pathways, including both p53-independent and p53-dependent signaling mechanisms. [92][93][94] It has been reported that NF-kB is rapidly activated following DNA damage in cultured neurons in an IKK-ATM-and p53-independent manner. 95 Data in the latter study suggested that NF-kB acts upstream of p53 in acute cell death induced by DNA damage, but, on the other hand, NF-kB promotes cell survival when activated over a longer time period in the absence of severe DNA damage.…”

Signals from within: the DNA-damage-induced NF-κB response

“…The link between NF-kB and p53 upon genotoxic stress is one of the most controversial fields in DNA damage literature (see also further). Two schools exist, one claiming that p53 is a prerequisite for NF-kB induction and that p53-induced NF-kB activation plays a merely apoptotic role, 64,65 the other claiming that genotoxic stress-induced p53 and NF-kB activation represent two independent parallel pathways, both activated by ATM, which might however interfere with each other's action through distinct mechanisms. 42,66,67 The first argument is based on the fact that some authors showed that the p53-null tumour cell line Saos-2 is resistant to doxorubicin or etoposideinduced NF-kB activation, while doxocycline-induced expression of p53 restores NF-kB activation.…”

“…42,66,67 The first argument is based on the fact that some authors showed that the p53-null tumour cell line Saos-2 is resistant to doxorubicin or etoposideinduced NF-kB activation, while doxocycline-induced expression of p53 restores NF-kB activation. 65 The other school claims that p53-null cells such as Saos-2 or 10(1) murine embryo fibroblasts do activate NF-kB as efficiently as p53 wt cells in response to genotoxic stress. 42 The reason underlying these opposite results is at present not understood, but the numerous reports showing efficient NF-kB activation upon genotoxic stress in cell lines transformed with SV40 large T antigen (resulting in inactivation of p53) or in cell lines harbouring mutations in p53 make the absolute requirement for p53 in DNA damage-induced NF-kB activation rather unlikely (e.g., Panta et al 42 and Arlt et al 68 ).…”

“…66 Nevertheless, p53 induction in se (by doxoxyclin-mediated expression or transient overexpression) leads to a slow activation of NF-kB. Bohuslav et al 65 showed that this pathway occurs in an IkBa phosphorylation and IKK-independent way, involving activation of the ERK kinase and ribosomal S6 kinase pp90rsk (as judged by treatment with ERK inhibitors or siRNA for pp90rsk). These latter observations have been troubled by a report showing that DNA damage indeed leads to activation of ERK and pp90rsk, but in a p53-independent way.…”