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J. Biol. Chem., Vol. 280, Issue 21, 20604-20611, May 27, 2005

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Alternative Splicing of Vitamin D-24-Hydroxylase

A NOVEL MECHANISM FOR THE REGULATION OF EXTRARENAL 1,25-DIHYDROXYVITAMIN D SYNTHESIS^*

Songyang Ren, Lisa Nguyen, Shaoxing Wu, Carlos Encinas, John S. Adams, and Martin Hewison¶

From the Department of Medicine, Division of Endocrinology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048 and the Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom

Synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)₂D), by renal epithelial cells is tightly controlled during normal calcium homeostasis. By contrast, macrophage production of 1,25-(OH)₂D is often dysregulated with potential hypercalcemic complications. We have postulated that this is due to abnormal catabolism of 1,25-(OH)₂D by the feedback control enzyme, vitamin D-24-hydroxylase (CYP24). Using chick HD-11 and human THP-1 myelomonocytic cell lines, we have shown that macrophage-like cells express a splice variant of the CYP24 gene (CYP24-SV), which encodes a truncated protein. Compared with the holo-CYP24 gene product in chick and human cells (508 and 513 amino acids, respectively), the truncated CYP24-SV versions consisted of 351 and 372 amino acids. These CYP24-SV proteins retained intact substrate-binding domains but lacked mitochondrial targeting sequences and were therefore catalytically inactive. In common with CYP24, expression of the CYP24 variants was induced by 1,25-(OH)₂D but without a concomitant rise in 24-hydroxylase activity. However, overexpression of CYP24-SV in HD-11 and THP-1 cells reduced synthesis of 1,25-(OH)₂ D (40–50%), whereas antisense CYP24-SV expression increased 1,25-(OH)₂D production by 2–7-fold. These data suggest that alternative splicing of CYP24 leads to the generation of a dominant negative-acting protein that is catalytically dysfunctional. We theorize that expression of the CYP24-SV may contribute to the extracellular accumulation of 1,25(OH)₂D in human health and disease.

Received for publication, December 23, 2004 , and in revised form, March 22, 2005.

^* This work was supported by National Institutes of Health Grants AI40403, AR50626, and RR00425. 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.

The on-line version of this article (available at http://www.jbc.org) contains five appendices with figures.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF428109.

^¶ To whom correspondence should be addressed: Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom. Tel.: 44-121-414-3776; Fax: 44-121-415-8712; E-mail: M.Hewison{at}bham.ac.uk.

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