Induction of Apoptosis by Targeting the Microtubule Network: Using HIV Tat as a Model System

摘要

The transcriptionally active P-TEFb that phosphorylates RNA Polymerase II to stimulate general and HIV-specific transcriptional elongation is presumed to exist in a free cyclin T1/CDK9 heterodimer. About half of cellular cyclin T1/CDK9 are also found in an inactive complex containing the 7SK snRNA and the HEXIM1 protein. In this research, I show that the remaining half are associated with Brd4, a bromodomain protein that binds to acetylated histones. In stress-induced cells, the 7SK/HEXIM1-bound cyclin T1/CDK9 is quantitatively converted into the Brd4-associated form for stress-induced transcription. The association with Brd4 is essential to form the transcriptionally active P-TEFb and recruits P-TEFb to transcription templates in vivo and in vitro. Although generally required for transcription, the P-TEFb- recruitment function of Brd4 can be substituted by that of HIV-1 Tat, which recruits cyclin T1/CDK9 for activated HIV-1 transcription. The regulation of the general transcription factor P-TEFb by Brd4, HEXIM1 and 7SK is implicated in regulating cell growth, which may be related to the onset of cancer.