Perspective: Expanding role of cyclin dependent kinases in cytokine inducible gene expression

Abstract

The Positive Transcriptional Elongation Factor b (P-TEFb), a heterodimer of CDK9 and Cyclin T1, is widely implicated in control of basal gene expression. Here, P-TEFb is involved in transitioning paused RNA polymerase II to enter productive transcriptional elongation mode by phosphorylating negative elongation factors and Ser2 of the heptad repeat in the RNA Pol II COOH terminal domain (CTD). Recent work in two unrelated inducible signaling pathways have illustrated additional roles of P-TEFb in mediating cytokine inducible gene expression in TNF-inducible NF-B activation and IL-6-inducible STAT3 transcription networks. This perspective will illustrate some of the new concepts derived from these studies, illustrating the role of P-TEFb in inducible gene expression. In these signaling cascades, P-TEFb forms protein complexes with the activated nuclear transcription factor in the nucleoplasm, an association important for P-TEFb recruitment to downstream target genes. Studies using siRNA mediated knockdown and/or selective P-TEFb inhibitors have further shown that P-TEFb plays a role in activation of a subset of NF-B dependent targets. Interestingly, these P-TEFb sensitive genes are characterized by inducible RNA Pol II recruitment and this recruitment is dependent on CDK enzymatic activity. The potential of inhibiting P-TEFb as an anti-inflammatory therapy in innate immunity and systemic inflammation will be discussed.