title: Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression.
abstract: 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.
authors.affiliation: Institute of Pharmacology, Medical School Hannover, Hannover, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Buss
authors.forename: Katja
authors.initials: K
authors.lastname: Handschick
authors.forename: Nadine
authors.initials: N
authors.lastname: Jurrmann
authors.forename: Pirita
authors.initials: P
authors.lastname: Pekkonen
authors.forename: Knut
authors.initials: K
authors.lastname: Beuerlein
authors.forename: Helmut
authors.initials: H
authors.lastname: Müller
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
authors.forename: Jeremy
authors.initials: J
authors.lastname: Saklatvala
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Ojala
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
mesh_terms: D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013160:Splenic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053719:Tandem Mass Spectrometry; D013953:Thymus Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D051361:Cyclin-Dependent Kinase 6