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Stimulation of the collagen α1(I) endogenous gene and transgene in carbon tetrachloride–induced hepatic fibrosis

✍ Scribed by David A. Brenner; Linda Veloz; Rudolf Jaenisch; Joseph M. Alcorn


Publisher
John Wiley and Sons
Year
1993
Tongue
English
Weight
736 KB
Volume
17
Category
Article
ISSN
0270-9139

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✦ Synopsis


Cirrhosis is characterized by a marked increase in the deposition of type I collagen and in the expression of the type I collagen genes d ( 1 ) and &(I). Although al(1) gene regulation has been extensively studied in cultured cells, these results may not be applicable to hepatic fibrogenesis in uiuo. Therefore the regulation of the al(1) endogenous gene and an cul(1) transgene was studied in a transgenic mouse model that has a single copy of a human d ( I ) gene segment containing the structural gene and 1.6 Kb of 5' DNA and 20 Kb of 3' DNA. To initiate hepatic fibrogenesis, we treated mice with the hepatotoxin carbon tetrachloride, either in a single dose or in biweekly doses for a period of 3 to 8 wk. Subsequently, hepatic al(1) messenger RNA levels were determined by a species-specific RNase protection assay. Carbon tetrachloride injections coordinately increased the messenger RNA levels of the cul(1) endogenous gene and the transgene, both immediately and after 8 wk. These experiments demonstrate that this d ( I ) transgene fragment contains information sufficient for appropriate basal and carbon tetrachloride-stimulated hepatic expression. They further demonstrate that sufficient homology exists between the human and mouse regulatory elements for the recognition of human cis-acting elements by mouse trans-acting factors. Thus transgenic mice provide a unique model in which to characterize the collagen cul(1) regulatory elements that are required in uiuo for pathophysiological responses. (HEPATOLOGY 1993; 17:

287-292.)

Cirrhosis represents the final result of complex cellular and biochemical interactions in the liver (1-3). Type I collagen, which is a product of the genes d ( I > and a2(I), becomes the most abundant extracellular matrix


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