PLoS ONE (Jan 2012)

Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression.

  • Holger Buss,
  • Katja Handschick,
  • Nadine Jurrmann,
  • Pirita Pekkonen,
  • Knut Beuerlein,
  • Helmut Müller,
  • Robin Wait,
  • Jeremy Saklatvala,
  • Päivi M Ojala,
  • M Lienhard Schmitz,
  • Michael Naumann,
  • Michael Kracht

DOI
https://doi.org/10.1371/journal.pone.0051847
Journal volume & issue
Vol. 7, no. 12
p. e51847

Abstract

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Nuclear factor kappa-B (NF-κB) activates multiple genes with overlapping roles in cell proliferation, inflammation and cancer. Using an unbiased approach we identified human CDK6 as a novel kinase phosphorylating NF-κB p65 at serine 536. Purified and reconstituted CDK6/cyclin complexes phosphorylated p65 in vitro and in transfected cells. The physiological role of CDK6 for basal as well as cytokine-induced p65 phosphorylation or NF-κB activation was revealed upon RNAi-mediated suppression of CDK6. Inhibition of CDK6 catalytic activity by PD332991 suppressed activation of NF-κB and TNF-induced gene expression. In complex with a constitutively active viral cyclin CDK6 stimulated NF-κB p65-mediated transcription in a target gene specific manner and this effect was partially dependent on its ability to phosphorylate p65 at serine 536. Tumor formation in thymi and spleens of v-cyclin transgenic mice correlated with increased levels of p65 Ser536 phosphorylation, increased expression of CDK6 and upregulaton of the NF-κB target cyclin D3. These results suggest that aberrant CDK6 expression or activation that is frequently observed in human tumors can contribute through NF-κB to chronic inflammation and neoplasia.