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Papers In Press, published online ahead of print March 11, 2002
Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7038
Corresponding Author: stefbra{at}med.unc.edu
Collagen a1(I) mRNA is posttranscriptionally regulated in hepatic stellate cells (HSCs). Binding of protein factors to the evolutionary conserved stem-loop in the 5' UTR (5' stem-loop) is required for high level of expression in activated HSCs. The 5' stem-loop is also found in a2(I) and a1(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 which is transcribed from the optimized mouse U7 snRNA 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 a1(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 a1(I) mRNA. The decoy decreases collagen a1(I) mRNA expression by 50-60% during activation of HSCs. It also decreases collagen a2(I) mRNA expression and collagen a1(III) mRNA expression. The cellular level of collagen a1(I) propeptide, as well as disulfide bonded collagen type I trimer, are reduced by 70%. However, the p74WT decoy did not decrease a smooth muscle actin protein or the mRNA levels of GAPDH and IL-6. The p74WT decoy was also introduced into activated human HSCs. In these cells the decoy decreased collagen a1(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.
J. Biol. Chem, 10.1074/jbc.M108065200
Submitted on August 21, 2001
Revised on January 15, 2002
Accepted on March 8, 2002
Inhibition of collagen a1(I) expression by the 5' stem-loop as a molecular decoy
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