Abstract
Androgen receptor (AR) may communicate with the general transcription machinery on the core promoter to exert its function as a transcriptional modulator. Our previous report demonstrated that the AR interacted with transcription factor IIH (TFIIH) under physiological conditions and that overexpression of Cdk-activating kinase, the kinase moiety of TFIIH, enhanced AR-mediated transcription in prostate cancer cells. In an effort to further dissect the mechanisms implicated in AR transactivation, we report here that AR interacts with PITALRE, a kinase subunit of positive elongation factor b (P-TEFb). Cotransfection of the plasmid encoding the mutant PITALRE (mtPITALRE), defective in its RNA polymerase II COOH-terminal domain (CTD)-kinase activity, resulted in preferential inhibition of AR-mediated transactivation. Indeed, AR transactivation in PC-3 cells was preferentially inhibited at the low concentration of 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), a CTD kinase inhibitor. These results suggest that CTD phosphorylation may play an important role in AR-mediated transcription. Furthermore, a nuclear run-on transcription assay of the prostate-specific antigen gene, an androgen-inducible gene, showed that transcription efficiency of the distal region of the gene was enhanced upon androgen induction. Taken together, our reports suggest that AR interacts with TFIIH and P-TEFb and enhances the elongation stage of transcription.
Highlights
Molecular studies of eukaryotic transcription suggest that the process of transcription can be divided into the following steps: preinitiation complex assembly on the core promoter, initiation, promoter clearance, elongation, and termination [1]
In an effort to further dissect the mechanisms implicated in Androgen receptor (AR) transactivation, we found that AR interacts with PITALRE, a kinase subunit of positive elongation factor b (P-TEFb) [24], and that cotransfection of the plasmid encoding the mutant PITALRE, which is defective in its COOH-terminal domain (CTD) kinase activity [25], results in preferential inhibition of AR-mediated transactivation
AR is required to communicate with the general transcription machinery on the core promoter to exert its function as a transcriptional modulator
Summary
Molecular studies of eukaryotic transcription suggest that the process of transcription can be divided into the following steps: preinitiation complex assembly on the core promoter, initiation, promoter clearance, elongation, and termination [1]. Activators may interact with auxiliary factors, called coregulators, to enhance recruitment of the general transcription machinery on the promoter [6, 7]. It has been proposed that coregulators function as a bridge between activators and the basal transcription machinery [5,6,7] They may potentiate transactivation of nuclear receptors in transient transfection or in in vitro transcription assays through the modification of nucleosomal structure or the efficient recruitment of basal transcription machinery [6, 7]. A growing number of coregulators, such as SRC-1, ACTR, and PCAF, of steroid receptors have been reported to possess and/or recruit histone acetyltransferase activity to induce modification of nucleosomal structures leading to activation of transcription [6]. The molecular mechanism by which activation function-1 synergistically activates transcription remains unclear
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