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Vol. 14, Issue 6, 2327-2341, June 2003

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Cell and Molecular Regulation of Endothelin-1 Production during Hepatic Wound Healing

Rong Shao ^*, Zengdun Shi ^*, Philip J. Gotwals , Victor E. Koteliansky , Jacob George  , and Don C. Rockey ^* ||

^* Duke University Liver Center and the Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710; Liver Center Laboratory and the Department and Medicine, University of California, San Francisco, San Francisco, California; and Biogen, Inc, Cambridge, Massachusetts 02142

Submitted June 7, 2002; Revised December 3, 2003; Accepted February 26, 2003
Monitoring Editor: Carl-Henrik Heldin

During hepatic wound healing, activation of key effectors of the wounding response known as stellate cells leads to a multitude of pathological 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. Herein, we demonstrate up-regulation of 56- and 62-kDa ECE-1 3'-untranslated region (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 base pairs (the 56-kDa protein) and to a region between 60 and 193 base pairs 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, transforming growth factor-1, 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 lead to ECE-1 mRNA stabilization in stellate cells via binding of 56- and 62-kDa proteins, which in turn are regulated by transforming growth factor-. The possibility that the same or similar regulatory events are present in other forms of wound healing is raised.

Present address: Storr Liver Unit, Department of Medicine, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia.

^|| Corresponding author. E-mail address: don.rockey{at}duke.edu.

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