Article

Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65.

Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.
Cell death and differentiation (impact factor: 8.24). 11/2009; 17(4):689-98. DOI:10.1038/cdd.2009.174 pp.689-98
Source: PubMed

ABSTRACT Post-translational modification and degradation of proteins by the ubiquitin-proteasome system are key regulatory mechanisms in cellular responses to various stimuli. The NF-kappaB signaling pathway is controlled by the ubiquitin-mediated proteolysis. RelA/p65, which is a main subunit of NF-kappaB, is ubiquitinated for degradation by SOCS-1, but the functional mechanism of its ubiquitination remains poorly understood. In this study we show that phosphorylation of RelA/p65 at Ser276 prevents its degradation by ubiquitin-mediated proteolysis. In contrast, impairment of Ser276 phosphorylation affects constitutive degradation of RelA/p65. Importantly, we identify Pim-1 as a further kinase responsible for the phosphorylation of RelA/p65 at Ser276. Depletion of Pim-1 hinders not only Ser276 phosphorylation but also transactivation of RelA/p65 target genes. We also show that Pim-1 contributes to recruitment of RelA/p65 to kappaB-elements to activate NF-kappaB signalling after TNF-alpha stimulation. In concert with these results, the knockdown of Pim-1 impairs IL-6 production and augments apoptosis by interfering RelA/p65 activation. These findings provide a model in which Pim-1 phosphorylation of RelA/p65 at Ser276 allows defense against ubiquitin-mediated degradation and whereby exerts activation of NF-kappaB signalling.

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Keywords

activate NF-kappaB signalling
 
augments apoptosis
 
cellular responses
 
defense
 
kinase responsible
 
main subunit
 
NF-kappaB
 
NF-kappaB signaling pathway
 
NF-kappaB signalling
 
Pim-1 contributes
 
Pim-1 hinders
 
Pim-1 impairs IL-6 production
 
Pim-1 phosphorylation
 
Post-translational modification
 
RelA/p65 activation
 
RelA/p65 target genes
 
SOCS-1
 
TNF-alpha stimulation
 
ubiquitin-proteasome system
 
various stimuli
 

K Nihira