Cyclin-Dependent Kinases as Coregulators of Inflammatory Gene Expression

Cyclin-dependent kinases (CDKs) exert a variety of functions through regulation of the cell cycle and gene expression, thus implicating them in diverse biological processes. Recent studies have deciphered the molecular mechanisms employed by nuclear CDKs to support the expression of inflammatory mediators. Induced transcription of many proinflammatory genes is increased during the G1 phase of the cell cycle in a CDK-dependent manner. This process involves the cytokine-induced recruitment of CDK6 to the nuclear chromatin fraction where it associates with transcription factors of the NF-κB, STAT, and AP-1 families. The ability of CDK6 to trigger the expression of VEGF-A and p16INK4A and to recruit the NF-κB subunit p65 to its target sites is largely independent of its kinase function. The involvement of CDKs in proinflammatory gene expression also allows therapeutic targeting of their functions to interfere with tumor-promoting inflammation or chronic inflammatory diseases.

TrendsCDKs in complex with various cyclins typically regulate the cell cycle or general RNA polymerase II functions during gene transcription.Emerging data suggest that the CDKs 1, 2, 4, 6, 7, 9 and their regulators (cyclins, INK, and CIP/KIP proteins) have additional functions in regulating the inflammatory response.CDK-dependent modulation of inflammatory genes in terminally differentiated immune cells occurs independently of the cell cycle.Chromatin-associated CDKs interact with members of the NF-κB, STAT, and AP-1-families of inflammatory transcription factors through kinase-dependent and -independent mechanisms.Therapeutic targeting of CDKs is predicted to affect cell migration, immune cell activation, neoangiogenesis, and inflammation, in addition to inhibiting cell proliferation.