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A more recent version of this article appeared on June 1, 2003
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Submitted on June 7, 2002
Revised on December 3, 2002
Accepted on February 26, 2003
1 Duke University Liver Center and the Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, NC 27710
2 Biogen, Inc, Cambridge, MA 02142
3 Liver Center Laboratory and the Department and Medicine, University of California, San Francisco
* Corresponding author. E-mail address: dcrockey{at}acpub.duke.edu.
During hepatic wound healing, activation of key effectors of the wounding response known as stellate cells leads to a multitude of pathologic processes, including increased production of endothelin-1 (ET-1). This latter process has been linked to enhanced expression of endothelin converting enzyme-1 (ECE-1, the enzyme that converts precursor ET-1 to the mature peptide) in activated stellate cells. Here, we demonstrate up-regulation of 56 kDa and 62 kDa ECE-1 3' UTR mRNA binding proteins in stellate cells after liver injury and stellate cell activation. Binding of these proteins was localized to a CC rich region in the proximal ECE-1 3' UTR bp (the 56 kDa protein) and to a region between 60-193 bp in the ECE-1 3' UTR mRNA (62 kDa). A functional role for the 3' UTR mRNA/protein interaction was established in a series of reporter assays. Additionally, TGF-
?, a cytokine integral to wound healing, stimulated ET-1 production. This effect was due to ECE-1 mRNA stabilization and increased ECE-1 expression in stellate cells which, in turn was a result of de novo synthesis of the identified 56 and 62 kDa ECE-1 3' UTR mRNA binding proteins. These data indicate that liver injury and the hepatic wound healing response leads to ECE-1 mRNA stabilization in stellate cells via binding of 56 and 62 kDa proteins, which in turn are regulated by TGF-. The possibility that the same or similar regulatory events are present in other forms of wound healing is raised.
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