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Transcriptional Activation of Human CYP17 in H295R Adrenocortical Cells Depends on Complex Formation among p54^nrb/NonO, Protein-Associated Splicing Factor, and SF-1, a Complex That Also Participates in Repression of Transcription

Department of Biochemistry and Center in Toxicology, Vanderbilt University School of Medicine (M.B.S., V.Q.N., N.K., M.R.W.), Nashville, Tennessee 37232-0146; and Molecular Genetics and Microbiology, University of Texas (C.-J.H., P.W.T.), Austin, Texas 78705

Address all correspondence and requests for reprints to: Dr. Marion B. Sewer, Department of Biochemistry, Vanderbilt University School of Medicine, 606 Light Hall, Nashville, Tennessee 37232-0146. E-mail: . marion{at}toxicology.mc.vanderbilt.edu

The first 57 bp upstream of the transcription initiation site of the human CYP17 (hCYP17) gene are essential for both basal and cAMP-dependent transcription. EMSA carried out by incubating H295R adrenocortical cell nuclear extracts with radiolabeled -57/-38 probe from the hCYP17 promoter showed the formation of three DNA-protein complexes. The fastest complex contained steroidogenic factor (SF-1) and p54^nrb/NonO, the intermediate complex contained p54^nrb/NonO and polypyrimidine tract-binding protein-associated splicing factor (PSF), and the slowest complex contained an SF-1/PSF/p54^nrb/NonO complex. (Bu)₂cAMP treatment resulted in a cAMP-inducible increase in the binding intensity of only the upper complex and also activated hCYP17 gene transcription. SF-1 coimmunoprecipitated with p54^nrb/NonO, indicating direct interaction between these proteins. Functional assays revealed that PSF represses basal transcription. Further, the repression of hCYP17 promoter-reporter construct luciferase activity resulted from PSF interacting with the corepressor mSin3A. Trichostatin A attenuated the inhibition of basal transcription, suggesting that a histone deacetylase interacts with the SF-1/PSF/p54^nrb/NonO/mSin3A complex. Our studies lend support to the idea that the balance between transcriptional activation and repression is essential in the control of adrenocortical steroid hormone biosynthesis.

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