Functional Cooperation between CCAAT/Enhancer-Binding Proteins and the Vitamin D Receptor in Regulation of 25-Hydroxyvitamin D sub(3) 24-Hydroxylase

• Published in: Molecular and cellular biology Vol. 25; no. 1; pp. 472 - 487
• Main Authors: Dhawan, Puneet, Peng, Xiaorong, Sutton, Amelia LM, Macdonald, Paul N, Croniger, Colleen M, Trautwein, Christian, Centrella, Michael, Mccarthy, Thomas L, Christakos, Sylvia
• Format: Journal Article
• Language: English
• Published: 01.01.2005
• ISSN: 0270-7306

1,25-Dihydroxyvitamin D sub(3) [1,25(OH) sub(2)D sub(3)] induces the synthesis of 25-hydroxyvitamin D sub(3) 24-hydroxylase [24(OH)ase], an enzyme involved in its catabolism, thereby regulating its own metabolism. Here we demonstrate that CCAAT enhancer binding protein beta (C/EBP beta ) is induced by 1,25(OH) sub(2)D sub(3) 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) sub(2)D sub(3) induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBP beta . Suppression of 1,25(OH) sub(2)D sub(3)-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBP beta super(-/-) 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/EBP beta binding and markedly attenuated the transcriptional response to C/EBP beta . We also report the cooperation of CBP/p300 with C/EBP beta in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH) sub(2)D sub(3) but also parathyroid hormone (PTH) can induce C/EBP beta expression in osteoblastic cells. PTH potentiated the induction of C/EBP beta and 24(OH)ase expression in response to 1,25(OH) sub(2)D sub(3) in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBP beta 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) sub(2)D sub(3)-induced transcription. These findings also indicate a novel role for C/EBP beta in the cross talk between PTH and 1,25(OH) sub(2)D sub(3) that involves the regulation of VDR transcription.