Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression
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 phosphorylate...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2012
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| _version_ | 1797066077936549888 |
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| author | Buss, H Handschick, K Jurrmann, N Pekkonen, P Beuerlein, K Müller, H Wait, R Saklatvala, J Ojala, P Schmitz, M Naumann, M Kracht, M |
| author_facet | Buss, H Handschick, K Jurrmann, N Pekkonen, P Beuerlein, K Müller, H Wait, R Saklatvala, J Ojala, P Schmitz, M Naumann, M Kracht, M |
| author_sort | Buss, H |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:37:14Z |
| format | Journal article |
| id | oxford-uuid:46ac7aa8-4528-4b4d-902d-cfb9c59aebf2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:37:14Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:46ac7aa8-4528-4b4d-902d-cfb9c59aebf22022-03-26T15:15:12ZCyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expressionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:46ac7aa8-4528-4b4d-902d-cfb9c59aebf2EnglishSymplectic Elements at OxfordPublic Library of Science2012Buss, HHandschick, KJurrmann, NPekkonen, PBeuerlein, KMüller, HWait, RSaklatvala, JOjala, PSchmitz, MNaumann, MKracht, MNuclear 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. |
| spellingShingle | Buss, H Handschick, K Jurrmann, N Pekkonen, P Beuerlein, K Müller, H Wait, R Saklatvala, J Ojala, P Schmitz, M Naumann, M Kracht, M Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression |
| title | Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression |
| title_full | Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression |
| title_fullStr | Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression |
| title_full_unstemmed | Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression |
| title_short | Cyclin-dependent kinase 6 phosphorylates NF-κB P65 at serine 536 and contributes to the regulation of inflammatory gene expression |
| title_sort | cyclin dependent kinase 6 phosphorylates nf κb p65 at serine 536 and contributes to the regulation of inflammatory gene expression |
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