| Autor: |
Buss, Holger, Handschick, Katja, Jurrmann, Nadine, Pekkonen, Pirita, Beuerlein, Knut, Müller, Helmut, Wait, Robin, Saklatvala, Jeremy, Ojala, Päivi M., Schmitz, M. Lienhard, Naumann, Michael, Kracht, Michael, Justus Liebig University Giessen |
| Rok vydání: |
2012 |
| Předmět: |
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| DOI: |
10.22029/jlupub-9060 |
| Popis: |
Nuclear 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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