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J. Biol. Chem., Vol. 281, Issue 51, 39114-39120, December 22, 2006

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Functional Characterization of Heterogeneous Nuclear Ribonuclear Protein C1/C2 in Vitamin D Resistance

A NOVEL RESPONSE ELEMENT-BINDING PROTEIN^*

From the Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048

Clinically apparent hereditary vitamin D-resistant rickets (HVDRR) usually results from a loss of function mutation in the vitamin D receptor (VDR). We recently described a human with the classical HVDRR phenotype but normal VDR function. Hormone resistance resulted from constitutive overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) that competed with a normally functioning VDR-retinoid X receptor (RXR) dimer for binding to the vitamin D response element (VDRE). Here we describe the purification, molecular cloning, and expression of this vitamin D resistance-causing, competitive response element-binding protein (REBiP) hnRNP C1/C2. When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%, respectively; both p < 0.005). By contrast, transient expression of an hnRNP C1/C2 small interfering RNA increased VDR transactivation by 39% (p < 0.005). Chromatin immunoprecipitation of nucleoproteins bound to the transcriptionally active 1,25-dihydroxy vitamin D-driven CYP24 promoter revealed the presence of REBiP in vitamin D-responsive human cells and indicated that the normal pattern of 1,25-dihydroxy vitamin D-initiated cyclical movement of the VDR on and off the VDRE is legislated by competitive, reciprocal occupancy of the VDRE by hnRNP C1/C2. The temporal and reciprocal pattern of VDR and hnRNPC1/C2 interaction with the VDRE was lost in HVDRR cells overexpressing the hnRNP C1/C2 REBiP. These observations provide further evidence for the functional importance of REBiP as a component of the multiprotein complex involved in the regulation of vitamin D-mediated transcription. In particular, chromatin immunoprecipitation data suggest that, in addition to its RNA-processing functions, hnRNP C1/C2 may be a key determinant of the temporal patterns of VDRE occupancy.

Received for publication, August 21, 2006 , and in revised form, October 27, 2006.

^* This work was supported by National Institutes of Health Grant R01AR37399 (to J. S. A.). 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 To whom correspondence should be addressed: Div. of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Ctr., 8700 Beverly Blvd., Rm. B-131, Los Angeles, CA 90048. Tel.: 310-423-8970; Fax: 310-423-0440; E-mail: adamsj{at}cshs.or.

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