Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/27541
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Type: Journal article
Title: Molecular action of 1,25-dihydroxyvitamin D3 and phorbol ester on the activation of the rat cytochrome P450C24 (CYP24) promoter: role of MAP kinase activities and identification of an important transcription factor binding site
Author: Nutchey, B.
Kaplan, J.
Dwivedi, P.
Omdahl, J.
Ferrante, A.
May, B.
Hii, C.
Citation: Biochemical Journal, 2005; 389(Part 3):753-762
Publisher: Portland Press
Issue Date: 2005
ISSN: 0264-6021
1470-8728
Statement of
Responsibility: 
Barbara K. Nutchey, Josef S. Kaplan, Prem P. Dwivedi, John L. Omdahl, Antonio Ferrante, Brian K. May, and Charles S. T. Hii
Abstract: Although investigations of the transcriptional regulation of the rat cytochrome P450C24 [CYP24 (25-hydroxyvitamin D3 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 JNK (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 ERK1(K71R) mutant (where K71R stands for Lys71-->Arg), which resulted in a reduced level of synergy on a CYP24 promoter-luciferase 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 JNK 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 JNK on the CYP24 gene promoter.
Keywords: Cell Line
Animals
Humans
Rats
Tetradecanoylphorbol Acetate
Calcitriol
Steroid Hydroxylases
Mitogen-Activated Protein Kinase Kinases
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinases
JNK Mitogen-Activated Protein Kinases
Protein Kinase C
Transcription Factors
Transcription, Genetic
Enzyme Induction
Binding Sites
Enzyme Activation
Promoter Regions, Genetic
Vitamin D3 24-Hydroxylase
Description: Copyright The Biochemical Society, London
DOI: 10.1042/BJ20041947
Appears in Collections:Aurora harvest 6
Molecular and Biomedical Science publications

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