期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 25, 期 1, 页码 472-487出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.25.1.472-487.2005
关键词
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资金
- NIDDK NIH HHS [R01 DK053980, R01 DK038961, R01 DK038961-15, DK 56310, R01 DK056310, DK 38961, DK 53980] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007250] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK053980, R01DK038961, R01DK056310] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007250] Funding Source: NIH RePORTER
1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] induces the synthesis of 25-hydroxyvitamin D-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/EBPbeta) is induced by 1,25(OH)(2)D-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)2D3 induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBPbeta. Suppression of 1,25(OH)(2)D-3-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBPbeta(-/-) 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/EBPbeta binding and markedly attenuated the transcriptional response to C/EBPbeta. We also report the cooperation of CBP/p300 with C/EBPbeta in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH)(2)D-3 but also parathyroid hormone (PTH) can induce C/EBPbeta expression in osteoblastic cells. PTH potentiated the induction of C/EBPbeta and 24(OH)ase expression in response to 1,25(OH)(2)D-3 in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBPbeta 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)(2)D-3-induced transcription. These findings also indicate a novel role for C/EBPbeta in the cross talk between PTH and 1,25(OH)(2)D-3 that involves the regulation of VDR transcription.
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