Regulation of NF-κB by Cyclin-Dependent Kinases Associated with the p300 Coactivator

TLDR

NF‑κB is a heterodimeric transcription factor activated by cytokines and stress, with the RelA(p65) subunit driving transcription of diverse genes. Interaction of NF‑κB with CDKs via the p300 and CBP coactivators coordinates transcriptional activation with cell‑cycle progression. Specific CDKs regulate NF‑κB transcriptional activation through interactions with the coactivator p300, and inhibition of CDK activity by p21 or a dominant‑negative Cdk2 enhances kappaB‑dependent gene expression, especially when p300 is co‑expressed.

Abstract

The nuclear factor kappaB (NF-kappaB) transcription factor is responsive to specific cytokines and stress and is often activated in association with cell damage and growth arrest in eukaryotes. NF-kappaB is a heterodimeric protein, typically composed of 50- and 65-kilodalton subunits of the Rel family, of which RelA(p65) stimulates transcription of diverse genes. Specific cyclin-dependent kinases (CDKs) were found to regulate transcriptional activation by NF-kappaB through interactions with the coactivator p300. The transcriptional activation domain of RelA(p65) interacted with an amino-terminal region of p300 distinct from a carboxyl-terminal region of p300 required for binding to the cyclin E-Cdk2 complex. The CDK inhibitor p21 or a dominant negative Cdk2, which inhibited p300-associated cyclin E-Cdk2 activity, stimulated kappaB-dependent gene expression, which was also enhanced by expression of p300 in the presence of p21. The interaction of NF-kappaB and CDKs through the p300 and CBP coactivators provides a mechanism for the coordination of transcriptional activation with cell cycle progression.