%0 Journal Article
%T Complex effects of flavopiridol on the expression of primary response genes
%A Havva Keskin
%A Judit Garriga
%A Daphne Georlette
%A Xavier Gra£ża
%J Cell Division
%D 2012
%I BioMed Central
%R 10.1186/1747-1028-7-11
%X 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.The Positive Transcription Elongation Factor b (P-TEFb) is a complex of CDK9 and either cyclins T1, T2 or K [1-4]. P-TEFb is recruited to promoters by transcription factors and/o
%K Primary Response genes
%K Mitogenic stimuli
%K Quiescence
%K Transcription
%K CDK9
%K RNA polymerase II
%K CDKs
%K Control of gene expression
%U http://www.celldiv.com/content/7/1/11