Cyclin-dependent kinase 6 (CDK6) (CDK6)

Cyclin-dependent kinase 6 (CDK6) is a serine/threonine kinase that traditionally regulates the G1/S phase transition of the cell cycle by phosphorylating the retinoblastoma protein (Rb) (UniProt P53667). Beyond its canonical role in cell division, CDK6 acts as a critical transcriptional co-factor that interacts with the NF-κB subunit p65 (RELA) to drive the expression of inflammatory genes (Handschick et al., 2014, Blood). This CDK6–NF-κB p65–dependent inflammatory gene regulation involves the recruitment of CDK6 to the promoters of pro-inflammatory cytokines and adhesion molecules, such as IL-6 and ICAM-1, a function that is largely independent of its homolog CDK4 (Kollmann et al., 2013, Cancer Cell). In various cancers, particularly leukemias and lymphomas, as well as chronic inflammatory diseases, this pathway is frequently dysregulated, promoting tumor survival and an aggressive inflammatory microenvironment (PubMed: 24366334). Therapeutic targeting of CDK6 with small-molecule inhibitors like palbociclib, ribociclib, and abemaciclib effectively blocks both its kinase activity and its ability to facilitate NF-κB-mediated transcription (PubChem CID 5330286). Consequently, CDK6 is a dual-purpose target whose inhibition can arrest the cell cycle and suppress pathological inflammation simultaneously.

Other names

Cell division protein kinase 6Serine/threonine-protein kinase PLSTIRECDK6-p65 complexRELA-CDK6 interactionCDK6–NF-κB p65–dependent inflammatory gene regulation

Inhibition of the catalytic activity of CDK6 and disruption of its scaffolding role in the NF-κB p65 transcriptional complex at inflammatory gene promoters.