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Molecular and Cellular Biology, April 2000, p. 2818-2826, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The DNA Binding Protein BTEB Mediates Acetaldehyde-Induced, Jun N-Terminal Kinase-Dependent alpha I(I) Collagen Gene Expression in Rat Hepatic Stellate Cells

Anping Chen and Bernard H. Davis*

Gastroenterology Section, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois 60637

Received 1 November 1999/Returned for modification 22 December 1999/Accepted 24 January 2000

Alcohol-induced cirrhosis results partially from the excessive production of collagen matrix proteins, which, predominantly alpha I(I) collagen, are produced and secreted by activated hepatic stellate cells (HSC). The accumulation of alpha I(I) collagen in HSC during cirrhosis is largely due to an increase in alpha I(I) collagen gene expression. Acetaldehyde, the major active metabolite of alcohol, is known to stimulate alpha I(I) collagen production in HSC. However, the mechanisms responsible for it remain unknown. The aim of this study was to elucidate the mechanisms by which alpha I(I) collagen gene expression is induced by acetaldehyde in rat HSC. In the present study, the acetaldehyde response element was located in a distal GC box, previously described as the UV response element, in the promoter of the alpha I(I) collagen gene (-1484 to -1476). The GC box was predominantly bound by the DNA binding transcription factor BTEB (basic transcription element binding protein), expression of which was acetaldehyde and UV inducible. Blocking BTEB protein expression significantly reduced the steady-state levels of the acetaldehyde-induced alpha I(I) collagen mRNA, suggesting that BTEB is required for this gene expression. Further studies found that acetaldehyde activated Jun N-terminal kinase (JNK) 1 and 2 and activator protein 1 (AP-1) transactivating activity. Inhibition of JNK activation resulted in the reduction of the acetaldehyde-induced BTEB protein abundance and alpha I(I) collagen mRNA levels, indicating that the expression of both genes is JNK dependent in HSC. Taken together, these studies demonstrate that BTEB mediates acetaldehyde-induced, JNK-dependent alpha I(I) collagen gene expression in HSC.

* Corresponding author. Mailing address: Gastroenterology Section, Department of Medicine, University of Chicago Medical Center, MC 4076, 5841 S. Maryland Ave., Chicago, IL 60637. Phone: (773) 702-1467. Fax: (773) 834-1288. E-mail: bhdavis{at}medicine.bsd.uchicago.edu.

Molecular and Cellular Biology, April 2000, p. 2818-2826, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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