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Molecular and Cellular Biology, January 2005, p. 472-487, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.472-487.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Puneet Dhawan,1 Xiaorong Peng,1 Amelia L. M. Sutton,2 Paul N. MacDonald,2 Colleen M. Croniger,3 Christian Trautwein,4 Michael Centrella,5 Thomas L. McCarthy,5 and Sylvia Christakos1*

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.

* Corresponding author. Mailing address: UMDNJ-New Jersey Medical School, Dept. of Biochemistry and Molecular Biology, 185 South Orange Ave., Newark, NJ 07103 Phone: (973) 972-4033. Fax: (973) 972-5594. E-mail: christak{at}umdnj.edu.

Molecular and Cellular Biology, January 2005, p. 472-487, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.472-487.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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