Disease relevance of Cdk9

• Our results suggest that P-TEFb represents an attractive target for the development of novel HIV therapeutics [1].

High impact information on Cdk9

• P-TEFb, a heterodimer of the kinase Cdk9 and cyclin T, was isolated as a factor that stimulates formation of productive transcription elongation complexes in vitro [2].
• The transition from abortive into productive elongation is proposed to be controlled by a positive transcription elongation factor b (P-TEFb) through phosphorylation of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II [3].
• Transfection experiments with wild-type or kinase knockout PITALRE demonstrated that P-TEFb is required for Tat function [1].
• We propose that P-TEFb phosphorylation of Pol II CTD coordinates transcription elongation with 3' end processing, and failure to do so leads to rapid RNA degradation [4].
• Here, we show that flavopiridol, a highly specific P-TEFb kinase inhibitor, dramatically reduces the global levels of Ser2--but not Ser5--phosphorylated CTD at actively transcribed loci on Drosophila polytene chromosomes under both normal and heat shocked conditions [4].

Biological context of Cdk9

• Cdk9 is an essential kinase in Drosophila that is required for heat shock gene expression, histone methylation and elongation factor recruitment [5].
• We knocked down the catalytic subunit of P-TEFb, Cdk9, in Drosophila melanogaster using RNA interference [5].

Associations of Cdk9 with chemical compounds

• We now name the large subunit cyclin T and the previously cloned small subunit (Zhu, Y. R., Peery, T., Peng, J. M., Ramanathan, Y., Marshall, N., Marshall, T., Amendt, B., Mathews, M. B., and Price, D. H. (1997) Genes Dev. 11, 2622-2632) cyclin-dependent kinase 9 (CDK9) [6].
• P-TEF is inhibited by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole at concentrations which have no effect on the initiation of transcription [7].
• We concluded that the flavonoid associates with P-TEFb with 1:1 stoichiometry even at concentrations of enzyme in the low nanomolar range [8].

Other interactions of Cdk9

• Like other CDKs, CDK9 is essentially inactive in the absence of its cyclin partner [6].

References