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YY1 Represses Vitamin D Receptor-Mediated 25-Hydroxyvitamin D₃ 24-Hydroxylase Transcription: Relief of Repression by CREB-Binding Protein

Department of Biochemistry and Molecular Biology University of Medicine and Dentistry of New Jersey-New Jersey Medical School Newark, New Jersey 07103

Ying Yang transcription factor (YY1) can repress or activate transcription. 25-Hydroxyvitamin D₃-24-hydroxylase [24(OH)ase], an enzyme involved in the catabolism of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃], is up-regulated at the transcriptional level by 1,25-(OH)₂D₃ to self-induce its deactivation. Here we report that YY1 can repress 1,25-(OH)₂D₃-induced 24(OH)ase transcription in CV1 cells transfected with vitamin D receptor (VDR) expression vector or in LLCPK₁ cells that contain VDR endogenously. With increasing amounts of YY1 DNA transfected (500 ng to 2 µg), ligand-dependent VDR activation of 24(OH)ase transcription was steadily repressed (maximum repression was 10-fold). Thus, YY1 may be a key modulator preventing activation at times that do not require the enzyme to be expressed. Relief of YY1 repression was observed in the presence of TFIIB or CBP (CREB binding protein) suggesting that YY1 may exert repression, in part, by sequestering TFIIB/CBP. Glutathione-S-transferase (GST) pull-down assays identified regions in the N and C termini of CBP that can bind YY1. In addition, the N-terminal region of CBP that interacts with YY1 can inhibit YY1 from binding to TFIIB. Thus, CBP may alleviate YY1-mediated repression, in part, by preventing YY1 from binding to TFIIB, which is required for VDR-mediated transcription. In summary, our results suggest that YY1 represses 24(OH)ase transcription, at least in part, by sequestering activator proteins involved in VDR-mediated transcription. In addition, our findings demonstrate a role for CBP in relief of repression of VDR-mediated transcription.

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