Journal
BIOCHEMICAL JOURNAL
Volume 389, Issue -, Pages 753-762Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20041947
Keywords
cytochrome P450C24; 1,25-dihydroxyvitamin D-3; extracellular-signal-regulated kinase 1/2 (ERK1/2); c-Jun N-terminal kinase (JNK); phorbol ester; transcriptional regulation
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Although investigations of the transcriptional regulation of the rat cytochrome P450C24 [CYP24 (25-hydroxyvitamin D-3 24-hydroxylase)] gene by 1,25D (1,25-dihydroxyvitamin D3) at either the genomic, or more recently at the non-genomic, level have provided insight into the mechanism of control of 1,25D levels, this regulation is still poorly characterized. Using HEK-293T cells (human embryonic kidney 293T cells), we reported that 1,25D induction of CYP24 requires INK (c-Jun N-terminal kinase) but not the ERK1/2 (extracellular-signal-regulated kinase 1/2). The phenomenon of synergistic up-regulation of CYP24 expression by PMA and 1,25D is well known and was found to be protein kinase C-dependent. Whereas ERK1/2 was not activated by 1,25D alone, its activation by PMA was potentiated by 1,25D also. The importance of ERK1/2 for transcriptional synergy was demonstrated by transfection of a dominant-negative ERK 1 (K71R) mutant (where K71R stands for Lys(71) -> Arg), which resulted in a reduced level of synergy on a CYP24 promoter-lunciferase construct. JNK was also shown to be required for synergy. We report, in the present study, the identification of a site located at - 171/ - 163, about 30 bp upstream of the vitamin D response element-1 in the CYP24 proximal promoter. This sequence, 5'-TGTCGGTCA-3', is critical for 1,25D induction of CYP24 and is therefore termed the vitamin D stimulatory element. The vitamin D stimulatory element, a target for the INK module, and an Ets-1 binding site were shown to be vital for synergy between PMA and 1,25D. This is the first report to identify the DNA binding sequences required for the synergy between PMA and 1,25D and a role for INK on the CYP24 gene promoter.
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