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Functional Cooperation between CCAAT/Enhancer-Binding Proteins and the Vitamin D Receptor in Regulation of 25-Hydroxyvitamin D₃ 24-Hydroxylase

Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey,¹ Departments of Pharmacology,² Nutrition, Case Western Reserve University, Cleveland, Ohio,³ Department of Gastroenterology and Hepatology, Medizinische Hochschule, Hannover, Germany,⁴ Department of Surgery, Yale University School of Medicine, New Haven, Connecticut⁵

Received 12 March 2004/ Returned for modification 15 April 2004/ Accepted 7 September 2004

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] induces the synthesis of 25-hydroxyvitamin D₃ 24-hydroxylase [24(OH)ase], an enzyme involved in its catabolism, thereby regulating its own metabolism. Here we demonstrate that CCAAT enhancer binding protein ß (C/EBPß) is induced by 1,25(OH)₂D₃ in kidney and in osteoblastic cells and is a potent enhancer of vitamin D receptor (VDR)-mediated 24(OH)ase transcription. Transfection studies indicate that 1,25(OH)₂D₃ induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBPß. Suppression of 1,25(OH)₂D₃-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBPß^–/– mice. A C/EBP site was identified at positions –395 to –388 (–395/–388) in the rat 24(OH)ase promoter. Mutation of this site inhibited C/EBPß binding and markedly attenuated the transcriptional response to C/EBPß. We also report the cooperation of CBP/p300 with C/EBPß in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH)₂D₃ but also parathyroid hormone (PTH) can induce C/EBPß expression in osteoblastic cells. PTH potentiated the induction of C/EBPß and 24(OH)ase expression in response to 1,25(OH)₂D₃ in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBPß in the protein kinase A-mediated induction of VDR transcription. From this study a fundamental role has been established for the first time for cooperative effects and cross talk between the C/EBP family of transcription factors and VDR in 1,25(OH)₂D₃-induced transcription. These findings also indicate a novel role for C/EBPß in the cross talk between PTH and 1,25(OH)₂D₃ that involves the regulation of VDR transcription.

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