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J. Biol. Chem., Vol. 283, Issue 37, 25606-25616, September 12, 2008

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Separate cis-trans Pathways Post-transcriptionally Regulate Murine CD154 (CD40 Ligand) Expression

A NOVEL FUNCTION FOR CA REPEATS IN THE 3'-UNTRANSLATED REGION^*

B. JoNell Hamilton, Xiao-Wei Wang, Jane Collins, Donald Bloch, Alan Bergeron^¶, Brian Henry, Benjamin M. Terry^||, Moe Zan¹, Andrew J. Mouland^**2, and William F. C. Rigby^¶3

From the Departments of Medicine and ^¶Microbiology and Immunology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, the Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, ^||New York Medical College, Valhalla, New York 10595, and the ^**Lady Davis Institute for Medical Research and McGill University, Montreal, Quebec H3T 1E2, Canada

We report a role for CA repeats in the 3'-untranslated region (3'-UTR) in regulating CD154 expression. Human CD154 is encoded by an unstable mRNA; this instability is conferred in cis by a portion of its 3'-UTR that includes a polypyrimidine-rich region and CA dinucleotide repeat. We demonstrate similar instability activity with the murine CD154 3'-UTR. This instability element mapped solely to a conserved 100-base CU-rich region alone, which we call a CU-rich response element. Surprisingly, the CA dinucleotide-rich region also regulated reporter expression but at the level of translation. This activity was associated with poly(A) tail shortening and regulated by heterogeneous nuclear ribonucleoprotein L levels. We conclude that the CD154 3'-UTR contains dual cis-acting elements, one of which defines a novel function for exonic CA dinucleotide repeats. These findings suggest a mechanism for the association of 3'-UTR CA-rich response element polymorphisms with CD154 overexpression and the subsequent risk of autoimmune disease.

Received for publication, March 31, 2008 , and in revised form, July 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01AR49834. This work was also supported by a grant from the American College of Rheumatology Research and Education Foundation. 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.

Deceased.

¹ Supported as a postdoctoral fellow on National Institutes of Health Training Grant T32AI07363.

² A Canadian Institutes of Health Research New Investigator.

³ To whom correspondence should be addressed. Tel.: 603-650-7700; Fax: 603-650-6223; E-mail: William.Rigby{at}Dartmouth.edu.

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