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

Cell Death Differ. 2010 Apr;17(4):689-98. doi: 10.1038/cdd.2009.174. Epub 2009 Nov 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / physiology
  • Animals
  • Apoptosis / physiology
  • COS Cells
  • Chlorocebus aethiops
  • Down-Regulation / physiology
  • Gene Expression Regulation / physiology
  • HeLa Cells
  • Humans
  • Interleukin-6 / metabolism
  • NF-kappa B / metabolism*
  • Phosphorylation / physiology
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • RNA Interference
  • Serine / metabolism
  • Signal Transduction / physiology*
  • Transcription Factor RelA / metabolism*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitin / metabolism*


  • Interleukin-6
  • NF-kappa B
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Ubiquitin
  • Serine
  • Proto-Oncogene Proteins c-pim-1