Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation.
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.
Lee
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DK
George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, Radiation Oncology, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
Duan
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HO
Chang
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D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D008954:Models, Biological; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B; D011233:Precipitin Tests; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D019473:Transcription Factors, TFII; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D008024:Ligands; D011944:Receptors, Androgen; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D004004:Dichlororibofuranosylbenzimidazole; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D017430:Prostate-Specific Antigen