Raf and Mitogen-activated Protein Kinase Regulate Stellate Cell Collagen Gene Expression

doi:10.1074/jbc.271.19.11039

Raf and Mitogen-activated Protein Kinase Regulate Stellate Cell Collagen Gene Expression (*)

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

^§ To whom correspondence should be addressed:
Gastroenterology Section, Dept. of Medicine, University of Chicago Medical Center, MC 4076, 5841 S. Maryland Ave., Chicago, IL 60637.
Tel.: 312-702-1467; Fax: 312-702-2182; bhdavis{at}medicine.bsd.uchicago.edu.

Abstract

Hepatic stellate cells become activated into myofibroblast-like cells during the early stages of hepatic injury associated with fibrogenesis. The subsequent dysregulation of hepatic stellate cell collagen gene expression is a central pathogenetic step during the development of cirrhosis. The cytoplasmic Raf and mitogen-activated protein (MAPK) kinases were found to differentially regulate αI(I) collagen gene expression in activated stellate cells. This suggests an unappreciated branch point exists between Raf and MAPK. A MAPK-stimulatory signal was mapped to the most proximal NF-1 and Sp-1 binding domains of the 5′-untranslated region of the collagen gene. A Raf-inhibitory signal was mapped to a further upstream binding domain involving a novel 60-kDa DNA-binding protein (p60). The cell-specific expression and induction of p60 in stellate cells during the early stages of hepatic fibrogenesis in vivo suggest a central role for this pathway during liver injury and stellate cell activation.

Footnotes

↵* This work was supported by National Institutes of Health Grants DK 02022, DK40223, DK 42086, DK 07074-18, and DK 47995-01A2 and by the Liver Research Fund, University of Chicago.
↵¹ The abbreviations used are:

MEK

MAPK kinase

MAPK

mitogen-activated protein kinase

5′-UTR

5′-untranslated region

AP-1

activator protein-1

HSC

hepatic stellate cell

TGFβ

transforming growth factor β

dn

dominant negative

NF-1

nuclear factor-1

FP-1

footprint 1

TAE

TGFβ activation element

CAT

chloramphenicol acetyltransferase

PAGE

polyacrylamide gel electrophoresis

bp

base pair(s)

kb

kilobase pair(s).
- Received January 23, 1996.
- Revision received February 29, 1996.