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J. Biol. Chem., Vol. 277, Issue 33, 29643-29653, August 16, 2002

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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^*

Prem P. Dwivedi, Charles S. T. Hii^§, Antonio Ferrante^§¶, Joseph Tan^§, Channing J. Der, John L. Omdahl^§§¶¶, Howard A. Morris, and Brian K. May

From the Departments of  Molecular Biosciences (Biochemistry), ^¶ Pediatrics and Physiology, University of Adelaide, Adelaide, Australia 5005, the ^§ Department of Immunopathology, Women's and Children's Hospital, North Adelaide, Australia 5005,  School of Pharmacy, Molecular and Biomedical Sciences, University of South Australia, Australia 5001, the  Department of Pharmacology, University of North Carolina at Chapel Hill, North Carolina 27599, the ^§§ Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, New Mexico 87131-5221, and the  Hanson Institute, Adelaide, Australia 5005

The current study investigated the action of 1,25-dihydroxyvitamin D₃ (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  (RXR) interacted with ERK2 but not ERK5 in intact cells, whereas Ets-1 interacted preferentially with ERK5. Increased phosphorylation of RXR and Ets-1 was detected in response to 1,25D. Activated ERK2 and ERK5 specifically phosphorylated RXR 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 (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 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.

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