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

Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1060, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 10/2008; 7(17):2661-6. DOI: 10.4161/cc.7.17.6594
Source: PubMed


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 Ser(2) of the heptad repeat in the RNA Pol II COOH terminal domain (CTD). This perspective will examine recent work in two unrelated inducible signaling pathways that illustrate the central role of P-TEFb in mediating cytokine inducible transcription networks. Specifically, P-TEFb has been recently discovered to play a key role in TNF-inducible NFkappaB activation and IL-6-inducible STAT3 signaling. In these signaling cascades, P-TEFb forms protein complexes with the activated nuclear RelA and STAT3 transcription factor in the cellular nucleoplasm, an association important for P-TEFb's promoter targeting. Studies using siRNA-mediated knockdown and/or selective CDK inhibitors show that P-TEFb plays a functional role in activation of a subset of NFkappaB-dependent targets and all STAT3-dependent genes studied to date. Interestingly, cytokine inducible genes that are sensitive to P-TEFb inhibition share an induction mechanism requiring inducible RNA Pol II recruitment. Chromatin immunoprecipitation studies have preliminarily indicated that 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.

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Available from: Allan R Brasier, Mar 10, 2014
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    • "Since inhibition of CDK9 activity is being explored as a therapeutic avenue in a number of diseases including AIDS, cancer, cardiac myopathies and inflammatory processes [11,18-20], it is important to examine the time dependent consequences of CDK9 inhibition on gene expression. To this end, we have determined the short and long term effects of FVP treatment on the expression of PRG mRNAs and the localization of RNAPII in these genes. "
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    ABSTRACT: The Positive Transcription Elongation Factor b (P-TEFb) is a complex of Cyclin Dependent Kinase 9 (CDK9) with either cyclins T1, T2 or K. The complex phosphorylates the C-Terminal Domain of RNA polymerase II (RNAPII) and negative elongation factors, stimulating productive elongation by RNAPII, which is paused after initiation. P-TEFb is recruited downstream of the promoters of many genes, including primary response genes, upon certain stimuli. Flavopiridol (FVP) is a potent pharmacological inhibitor of CDK9 and has been used extensively in cells as a means to inhibit CDK9 activity. Inhibition of P-TEFb complexes has potential therapeutic applications. It has been shown that Lipopolysaccharide (LPS) stimulates the recruitment of P-TEFb to Primary Response Genes (PRGs) and proposed that P-TEFb activity is required for their expression, as the CDK9 inhibitor DRB prevents localization of RNAPII in the body of these genes. We have previously determined the effects of FVP in global gene expression in a variety of cells and surprisingly observed that FVP results in potent upregulation of a number of PRGs in treatments lasting 4-24 h. Because inhibition of CDK9 activity is being evaluated in pre-clinical and clinical studies for the treatment of several pathologies, it is important to fully understand the short and long term effects of its inhibition. To this end, we determined the immediate and long-term effect of FVP in the expression of several PRGs. In exponentially growing normal human fibroblasts, the expression of several PRGs including FOS, JUNB, EGR1 and GADD45B, was rapidly and potently downregulated before they were upregulated following FVP treatment. In serum starved cells re-stimulated with serum, FVP also inhibited the expression of these genes, but subsequently, JUNB, GADD45B and EGR1 were upregulated in the presence of FVP. Chromatin Immunoprecipitation of RNAPII revealed that EGR1 and GADD45B are transcribed at the FVP-treatment time points where their corresponding mRNAs accumulate. These results suggest a possible stress response triggered by CDK9 inhibition than ensues transcription of certain PRGs. We have shown that certain PRGs are transcribed in the presence of FVP in a manner that might be independent of CDK9, suggesting a possible alternative mechanism for their transcription when P-TEFb kinase activity is pharmacologically inhibited. These results also show that the sensitivity to FVP is quite variable, even among PRGs.
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