Buss, HolgerHolgerBussHandschick, KatjaKatjaHandschickJurrmann, NadineNadineJurrmannPekkonen, PiritaPiritaPekkonenBeuerlein, KnutKnutBeuerleinMüller, HelmutHelmutMüllerWait, RobinRobinWaitSaklatvala, JeremyJeremySaklatvalaOjala, Päivi M.Päivi M.OjalaSchmitz, M. LienhardM. LienhardSchmitzNaumann, MichaelMichaelNaumannKracht, MichaelMichaelKracht2022-11-182013-03-042022-11-182012http://nbn-resolving.de/urn:nbn:de:hebis:26-opus-92322https://jlupub.ub.uni-giessen.de/handle/jlupub/9672http://dx.doi.org/10.22029/jlupub-9060Nuclear factor kappa-B (NF-kappaB) 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-kappaB 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-?B activation was revealed upon RNAi-mediated suppression of CDK6. Inhibition of CDK6 catalytic activity by PD332991 suppressed activation of NF-?B and TNF-induced gene expression. In complex with a constitutively active viral cyclin CDK6 stimulated NF-?B 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-?B target cyclin D3. These results suggest that aberrant CDK6 expression or activation that is frequently observed in human tumors can contribute through NF-?B to chronic inflammation and neoplasia.enNamensnennung 3.0 Internationalddc:610