Nuclear receptor 4A2 and C/EBP beta regulate the parathyroid hormone-mediated transcriptional regulation of the 25-hydroxyvitamin D3-1 alpha-hydroxylase

摘要

1 alpha-Hydroxylase is the enzyme responsible for the production, of the active form of vitamin D, 1,25-dihydroxyvitamin D-3. 1 alpha-Hydroxylase , found largely in the kidney, is known to be up-regulated by parathyroid hormone (PTH), however the mechanism of action of PTH and any required transcription factors have not been clearly identified. During gene array analysis we observed that NR4A2,, a nuclear orphan receptor, is markedly up-regulated in a porcine kidney cell line (AOK-B50) following PTH stimulation. NR4A2 overexpression increases the endogenous induction of 1 alpha-hydroxylase mRNA in the absence of PTH, however optimal stimulation is achieved when both NR4A2 and PTH are present. An unconventional site of action of NR4A2 was localized to a fragment comprising the sequence from -35/+22 of the la-hydroxylase promoter at a C/EBP consensus site. Study of the involvement of C/EBP beta, in the 1 alpha-hydroulase regulation revealed that the transcriptional enhancement by NR4A2 on the la-hydroxylase promoter is inhibited by C/EBP beta, In addition, C/EBP beta over-expression decreases the endogenous levels of both NR4A2 and lot-hydroxylase mRNA. (c) 2006 Elsevier Inc. All rights reserved.