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Integration of hormone signaling in the regulation of human 25(OH)D₃ 24-hydroxylase transcription

Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103

Submitted 13 May 2003 ; accepted in final form 4 December 2003

The current study sought to define the molecular mechanisms involved in the cross talk between 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and activators of PKC in the regulation of 25(OH)D₃ 24-hydroxlyase [24(OH)ase]. Transfection of the h24(OH)ase promoter construct [-5,500/-22 luciferase; vitamin D response elements at -294/-274 and -174/-151; AP-1 site at -1,167/-1,160] in vitamin D receptor (VDR)-transfected COS-7 cells resulted in strong activation by 1,25(OH)₂D₃. In these cells, cotreatment with the PKC activator TPA and 1,25(OH)₂D₃ yielded a 27-fold increase in luciferase activity, which was 2- to 3-fold greater than activation obtained with 1,25(OH)₂D₃ alone (P < 0.05). Similar results were observed using LLCPK-1 kidney cells, suggesting that the previously observed enhancement of 1,25(OH)₂D₃-induced renal 24(OH)ase mRNA and activity by PKC activation occurs at the level of transcription. The functional cooperation between PKC activation and VDR was not found to be mediated by the AP-1 site in the h24(OH)ase promoter or by enhanced binding of GRIP or DRIP205 to VDR and was also not due to PKC-mediated phosphorylation of VDR on Ser⁵¹. Our study demonstrates that, in LLCPK-1 kidney cells, the PKC enhancement of 1,25(OH)₂D₃-stimulated transcription may be due, in part, to an increase in VDR concentration. In addition, inhibitors of the MAPK pathway were found to decrease the TPA enhancement (P < 0.05). Because activation of MAPK has been reported to result in the phosphorylation of SRC-1 and in functional cooperation between SRC-1 and CREB binding protein, we propose that the potentiation of VDR-mediated transcription may also be mediated through changes in the phosphorylation of specific VDR coregulators.

1,25-dihydroxyvitamin D₃; vitamin D receptor; vitamin D regulation; phosphorylation; protein kinase C

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