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.

CDK6 as a key regulator of hematopoietic and leukemic stem cell activation

“…7 A subsequent report described CDK6 as a transcriptional coregulator of nuclear factor kB p65. 8 CDK6 appears to have a key role in hematopoietic tumors, where it is frequently upregulated. 5,7 CDK6 has also been shown to be critical in acute myeloid leukemia (AML) and acute lymphoblastic leukemia driven by mixed lineage leukemia fusion proteins.…”

Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

“…45 Since it has been reported that CDK6 may affect the transcriptional activity of NF-kB by its ability to phosphorylate the p65 subunit at serine 536, 50,51 we considered it interesting to evaluate whether this kinase could influence total levels of WNT5A. To address this issue we treated the cells with a known CDK6 activity inhibitor (PD332991).…”

Targeting CDK6 in cancer: State of the art and new insights

“…NF-kB induces the expression of pro-inflammatory genes. 20,21 Modulation of cell differentiation Despite the high level of homology between CDK4 and CDK6, there is an increasing list of distinct functions reported for CDK6. Among them is the ability of CDK6 to modulate differentiation in specific cell types including murine erythroid leukemia, primary mouse astrocytes, osteoblasts and osteoclasts, thymocytes, neurons, cardiomyocytes and hematopoietic cells.…”