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https://hdl.handle.net/2440/28178
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Type: | Journal article |
Title: | Role of MAP kinases in the 1,25-dihydroxyvitamin D3-induced transactivation of the rat cytochrome P450C24 (CYP24) promoter - Specific functions for ERK1/ERK2 and ERK5 |
Author: | Dwivedi, P. Hii, C. Ferrante, A. Tan, J. Der, C. Omdahl, J. Morris, H. May, B. |
Citation: | Journal of Biological Chemistry, 2002; 277(33):29643-29653 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2002 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Prem P. Dwivedi, Charles S. T. Hii, Antonio Ferrante, Joseph Tan, Channing J. Der, John L. Omdahl, Howard A. Morris and Brian K. May |
Abstract: | The current study investigated the action of 1,25-dihydroxyvitamin D(3) (1,25D) at the genomic and signal transduction levels to induce rat cytochrome P450C24 (CYP24) gene expression. A rat CYP24 promoter containing two vitamin D response elements and an Ets-1 binding site was used to characterize the mechanism of actions for the 1,25D secosteroid hormone. The Ets-1 binding site was determined to function cooperatively with the most proximal vitamin D response element in a hormone-dependent fashion. Evidence was obtained for distinct roles of ERK1/ERK2 and ERK5 in the 1,25D-inductive actions. Specifically, 1,25D stimulated the activities of ERK1/ERK2 and ERK5 in a Ras-dependent manner. Promoter induction was inhibited by mitogen-activated protein (MAP) kinase inhibitors (PD98059 and U0126) and a dominant-negative Ras mutant (Ras17N). Induction of CYP24 by 1,25D was also inhibited by overexpression of dominant-negative mutants of ERK1 and MEK5 (ERK1K71R and MEK5(A)). The p38 and JNK MAP kinases were not required for the action of 1,25D. 9-cis retinoid X receptor alpha (RXR alpha) interacted with ERK2 but not ERK5 in intact cells, whereas Ets-1 interacted preferentially with ERK5. Increased phosphorylation of RXR alpha and Ets-1 was detected in response to 1,25D. Activated ERK2 and ERK5 specifically phosphorylated RXR alpha and Ets-1, respectively. Mutagenesis of Ets-1 (T38A) reduced CYP24 promoter activity to levels observed with the dominant-negative MEK5(A) and inhibited ERK5-directed phosphorylation. Mutated RXR alpha (S260A) inhibited 1,25D-induced CYP24 promoter activity and abolished phosphorylation by activated ERK2. The 1,25D-inductive action through ERK5 involved Ets-1 phosphorylation at threonine 38, whereas hormone stimulation of ERK1/ERK2 required RXR alpha phosphorylation on serine 260. The ERK1/ERK2 and ERK5 modules provide a novel mechanism for linking the rapid signal transduction and slower transcription actions of 1,25D to induce CYP24 gene expression. |
Keywords: | COS Cells Animals Humans Rats Calcitriol Cytochrome P-450 Enzyme System Steroid Hydroxylases Mitogen-Activated Protein Kinases Two-Hybrid System Techniques Gene Expression Regulation, Enzymologic Promoter Regions, Genetic Transcriptional Activation Vitamin D3 24-Hydroxylase |
DOI: | 10.1074/jbc.M204561200 |
Published version: | http://dx.doi.org/10.1074/jbc.m204561200 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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