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Molecular and Cellular Biology, June 1999, p. 4334-4342, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Regulatory Role of the Conserved Stem-Loop Structure at the 5' End of Collagen alpha 1(I) mRNA

B. Stefanovic,* C. Hellerbrand, and D. A. Brenner

Departments of Medicine and Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Received 1 June 1998/Returned for modification 1 October 1998/Accepted 17 March 1999

Three fibrillar collagen mRNAs, alpha 1(I), alpha 2(I), and alpha 1(III), are coordinately upregulated in the activated hepatic stellate cell (hsc) in liver fibrosis. These three mRNAs contain sequences surrounding the start codon that can be folded into a stem-loop structure. We investigated the role of this stem-loop structure in expression of collagen alpha 1(I) reporter mRNAs in hsc's and fibroblasts. The stem-loop dramatically decreases accumulation of mRNAs in quiescent hsc's and to a lesser extent in activated hsc's and fibroblasts. The stem-loop decreases mRNA stability in fibroblasts. In activated hsc's and fibroblasts, a protein complex binds to the stem-loop, and this binding requires the presence of a 7mG cap on the RNA. Placing the 3' untranslated region (UTR) of collagen alpha 1(I) mRNA in a reporter mRNA containing this stem-loop further increases the steady-state level in activated hsc's. This 3' UTR binds alpha CP, a protein implicated in increasing stability of collagen alpha 1(I) mRNA in activated hsc's (B. Stefanovic, C. Hellerbrand, M. Holcik, M. Briendl, S. A. Liebhaber, and D. A. Brenner, Mol. Cell. Biol. 17:5201-5209, 1997). A set of protein complexes assembles on the 7mG capped stem-loop RNA, and a 120-kDa protein is specifically cross-linked to this structure. Thus, collagen alpha 1(I) mRNA is regulated by a complex interaction between the 5' stem-loop and the 3' UTR, which may optimize collagen production in activated hsc's.

* Corresponding author. Mailing address: University of North Carolina at Chapel Hill, Division of Digestive Diseases and Nutrition, CB 7038, 154 Glaxo Building, Chapel Hill, NC 27599. Phone: (919) 966-7885. Fax: (919) 966-7468. E-mail: cjc8{at}med.unc.edu.

Molecular and Cellular Biology, June 1999, p. 4334-4342, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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