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J. Biol. Chem., Vol. 282, Issue 3, 1544-1551, January 19, 2007

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Stress-induced c-Jun-dependent Vitamin D Receptor (VDR) Activation Dissects the Non-classical VDR Pathway from the Classical VDR Activity^*

Qing-Ping Li^¶12, Xiaomei Qi^¶1, Rocky Pramanik^¶, Nicole M. Pohl^¶, Mathew Loesch^¶, and Guan Chen^¶3

From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, the Department of Veterans Affairs, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, and the ^¶Department of Radiation Oncology, Loyola University of Chicago, Maywood, Illinois 60153

Vitamin D receptor (VDR) is a ligand-dependent transcription factor that mediates vitamin D₃-induced gene expression. Our previous work has established that stress MAPK signaling stimulates VDR expression (Qi, X., Pramank, R., Wang, J., Schultz, R. M., Maitra, R. K., Han, J., DeLuca, H. F., and Chen, G. (2002) J. Biol. Chem. 277, 25884–25892) and VDR inhibits cell death in response to p38 MAPK activation (Qi, X., Tang, J., Pramanik, R., Schultz, R. M., Shirasawa, S., Sasazuki, T., Han, J., and Chen, G. (2004) J. Biol. Chem. 279, 22138–22144). Here we show that c-Jun is essential for VDR expression and VDR in turn inhibits c-Jun-dependent cell death by non-classical mechanisms. In response to stress c-Jun is recruited to the Vdr promoter before VDR protein expression is induced. The necessary and sufficient role of c-Jun in VDR expression was established by the fact that c-Jun knock-out decreases VDR expression, whereas c-Jun restoration recovers its activity. Existence of the non-classical VDR pathway was suggested by a requirement of both c-Jun and VDR in stress-induced VDR activity and further demonstrated by VDR inhibiting c-Jun-dependent cell death independent of its classical transcriptional activity and independent of vitamin D₃. c-Jun is also required for vitamin D₃-induced classical VDR transcriptional activity by a mechanism likely involving physical interactions between c-Jun and VDR proteins. These results together reveal a non-classical mechanism by which VDR acts as a c-Jun/AP-1 target gene to modify c-Jun activity in stress response through increased protein expression independent of classical transcriptional regulations.

Received for publication, April 27, 2006 , and in revised form, September 14, 2006.

^* This work was supported by National Institutes of Health NCI Grant 2R01 CA91576, a Department of Veterans Affairs Merit Review Award, and the Charlotte Geyer Foundation (to G. C.). 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.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Pharmacology, Nanjing Medical University, Nanjing, China.

³ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel.: 414-456-8636; Fax: 414-456-6545; E-mail: gchen{at}mcw.edu.

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