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J. Biol. Chem., Vol. 279, Issue 45, 47298-47310, November 5, 2004

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The Functional Consequences of Cross-talk between the Vitamin D Receptor and ERK Signaling Pathways Are Cell-specific^*

Ramesh Narayanan, Veronica A. Tovar Sepulveda, Miriam Falzon, and Nancy L. Weigel¶

From the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and the Department of Pharmacology and Toxicology, Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas 77555

The actions of the active metabolite of 1,25-(OH)₂D₃ (1,25-D) are mediated primarily by the vitamin D receptor (VDR), a member of the nuclear receptor family of ligand-activated transcription factors. Although their ligands cause transcriptional activation, many of the ligands also rapidly activate cellular signaling pathways through mechanisms that have not been fully elucidated. We find that 1,25-D causes a rapid, but sustained activation of ERK (extracellular signal-regulated kinase) in bone cell lines. However, the effect of ERK activation on VDR transcriptional activity was cell line-specific. Inhibition of ERK activation by the MEK inhibitor, U0126, stimulated VDR activity in MC3T3-E1 cells, but inhibited the activity in MG-63 cells as well as in HeLa cells. VDR is not a known target of ERK. We found that the ERK target responsible for reduced VDR activity in MC3T3-E1 cells is RXR. MC3T3-E1 cells express lower levels of RXR and RXR than either HeLa or MG-63 cells. Although overexpression of RXR in MC3T3-E1 cells increased VDR activity, U0126 further enhanced the activity. In contrast, overexpression of RXR stimulated VDR activity but abrogated the stimulation by U0126. Thus, although 1,25-D treatment activates ERK in many cell types, subsequently inducing changes independent of VDR, the effects of treatment with 1,25-D on the transcriptional activity of VDR are RXR isoform-specific. In cells in which RXR is the VDR partner, the transcriptional activation of VDR by 1,25-D is attenuated by the concomitant activation of ERK. In cells utilizing RXR, ERK activation enhances VDR transcriptional activity.

Received for publication, April 13, 2004 , and in revised form, August 3, 2004.

^* This work was supported by The National Aeronautics and Space Administration (NASA) through the NASA Cooperative Agreement (NCC 9-58) with the National Space Biomedical Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6234; Fax: 713-790-1275; E-mail: nweigel{at}bcm.tmc.edu.

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