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J. Biol. Chem., Vol. 279, Issue 22, 23822-23829, May 28, 2004

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Regulation of 1(I) Collagen Messenger RNA Decay by Interactions with CP at the 3'-Untranslated Region^*

Jeffrey N. Lindquist, Christopher J. Parsons, Branko Stefanovic¶, and David A. Brenner||**

From the Biochemistry and Biophysics and Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, the ^||Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, the ^¶Department of Biomedical Sciences, Florida State University, Tallahassee, Florida 32306-4300, and the Scripps Research Institute, La Jolla, California 92037

Liver fibrosis is characterized by an increased deposition of extracellular matrix proteins, including collagen type I, by activated hepatic stellate cells (HSCs). Previous studies have shown that this increase is mediated primarily by a post-transcriptional mechanism. In particular, the RNA-binding protein CP binds to the 1(I) collagen 3'-untranslated region (UTR) and stabilizes this RNA in activated, but not quiescent, HSCs. This study examines the role of CP in the decay of transcripts containing the collagen 3'-UTR in extracts obtained from NIH fibroblasts and quiescent and activated HSCs. Using an in vitro decay system, CP binding activity was competed out with the addition of wild type oligonucleotides, but not with mutant oligonucleotides. Competition of CP binding activity increased the rate of decay of wild type transcripts containing the CP 3'-UTR binding site, but not of transcripts containing a mutated binding site. Quiescent HSC extracts contain no CP binding activity and have no difference in the rate of decay of transcripts with wild type and mutant binding sites for CP. The addition of recombinant CP was sufficient to increase the half-life of the wild type transcript, whereas that of the mutant transcript was minimally changed. In vitro decay assays performed with activated HSC extracts that contain CP binding activity demonstrate a markedly reduced decay rate of wild type compared with mutant transcripts. In vivo small interfering RNA experiments targeting CP showed a reduction of the binding activity of CP and a concomitant reduction in intracellular levels of 1(I) collagen messenger RNA. In conclusion, this study demonstrates the direct role of CP in the stabilization of 1(I) collagen messenger RNA by blocking RNA degradation in activated HSCs.

Received for publication, December 23, 2003

^* This work was supported by National Institutes of Health Grants AA12586-03, DK34987, and GM41804. 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 Medicine, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-5838; Fax: 212-305-9822; E-mail: dab2106{at}columbia.edu.

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