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Originally published In Press as doi:10.1074/jbc.M108065200 on March 11, 2002

J. Biol. Chem., Vol. 277, Issue 20, 18229-18237, May 17, 2002
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Inhibition of Collagen alpha 1(I) Expression by the 5' Stem-Loop as a Molecular Decoy*

Branko StefanovicDagger , Bernd Schnabl, and David A. Brenner

From the Departments of Medicine and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

Collagen alpha 1(I) mRNA is posttranscriptionally regulated in hepatic stellate cells (HSCs). Binding of protein factors to the evolutionary conserved stem-loop in the 5'-untranslated region (5' stem-loop) is required for a high level of expression in activated HSCs. The 5' stem-loop is also found in alpha 2(I) and alpha 1(III) mRNAs. Titration of the 5' stem-loop binding factors by a stably expressed RNA containing the 5' stem-loop (molecular decoy) may decrease the expression of these collagen mRNAs. We designed a 108-nt RNA that is transcribed from the optimized mouse U7 small nuclear RNA gene and contains the 5' stem-loop (p74WT decoy). This decoy accumulates in the nucleus and in the cytoplasm. When expressed in NIH 3T3 fibroblasts, the p74WT decoy decreased collagen alpha 1(I) mRNA level by 60% and decreased collagen type I secreted into the cellular medium by 50%. We also expressed this decoy in quiescent rat HSCs by adenoviral gene transfer. Quiescent HSCs undergo activation in culture, resulting in a 60-70-fold increase in collagen alpha 1(I) mRNA. The decoy decreases collagen alpha 1(I) mRNA expression by 50-60% during activation of HSCs. It also decreases collagen alpha 2(I) mRNA expression and collagen alpha 1(III) mRNA expression. The cellular levels of collagen alpha 1(I) propeptide and of disulfide-bonded collagen type I trimer are reduced by 70%. However, the p74WT decoy did not decrease alpha  smooth muscle actin protein or the mRNA levels of glyceraldehyde-3-phosphate dehydrogenase and interleukin-6. The p74WT decoy was also introduced into activated human HSCs. In these cells, the decoy decreased collagen alpha 1(I) propeptide and disulfide-bonded collagen trimer by 50-60%. These results indicate that the 5' stem-loop specifically regulates fibrillar collagen synthesis and represents a novel target for antifibrotic therapy. The molecular decoys provide a generalized method of assessing the functional significance of blocking the interactions of mRNA and proteins.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Division of Digestive Diseases and Nutrition, University of North Carolina, CB 7038, 154 Glaxo Bldg., Chapel Hill, NC 27599. Tel.: 919-966-7885; Fax: 919-966-7468; E-mail: stefbra@med.unc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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