title: Cyclin-dependent kinase 6 is a chromatin-bound cofactor for NF-κB-dependent gene expression.
abstract: Given the intimate link between inflammation and dysregulated cell proliferation in cancer, we investigated cytokine-triggered gene expression in different cell cycle stages. Transcriptome analysis revealed that G1 release through cyclin-dependent kinase 6 (CDK6) and CDK4 primes and cooperates with the cytokine-driven gene response. CDK6 physically and functionally interacts with the NF-κB subunit p65 in the nucleus and is found at promoters of many transcriptionally active NF-κB target genes. CDK6 recruitment to distinct chromatin regions of inflammatory genes was essential for proper loading of p65 to its cognate binding sites and for the function of p65 coactivators, such as TRIP6. Furthermore, cytokine-inducible nuclear translocation and chromatin association of CDK6 depends on the kinase activity of TAK1 and p38. These results have widespread biological implications, as aberrant CDK6 expression or activation that is frequently observed in human tumors modulates NF-κB to shape the cytokine and chemokine repertoires in chronic inflammation and cancer.
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Handschick
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Beuerlein
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Liane
authors.initials: L
authors.lastname: Jurida
authors.affiliation: Institute for Genetics, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Bartkuhn
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Müller
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Soelch
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Physiological Chemistry, Medical School Hannover, 30625 Hannover, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dittrich-Breiholz
authors.affiliation: Institute of Physiological Chemistry, Medical School Hannover, 30625 Hannover, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Scharfe
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Jarek
authors.affiliation: Institute of Biochemistry, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stellzig
authors.affiliation: Institute of Biochemistry, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, 35392 Giessen, Germany. Electronic address: michael.kracht@pharma.med.uni-giessen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051361:Cyclin-Dependent Kinase 6 / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D002843:Chromatin; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D007375:Interleukin-1; D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C495900:CDK4 protein, human