ZF9, A KRUPPEL-LIKE TRANSCRIPTION FACTOR UP-REGULATED IN-VIVO DURING EARLY HEPATIC-FIBROSIS

Wound repair in the liver induces altered gene expression in stellate cells (resident mesenchymal cells) in a process known as ''activation. '' A zinc finger transcription factor cDNA, zf9, was cloned from rat s tellate cells activated in vivo. Zf9 expression and biosynthesis are i ncreased markedly in activated cells in vivo compared with cells from normal rats (''quiescent'' cells), The factor is localized to the nucl eus and the perinuclear zone in activated but not quiescent cells. Zf9 mRNA also is expressed widely in nonhepatic adult rat tissues and the fetal liver. The zf9 nucleotide sequence predicts a member of the Kru ppel-like family with a unique N-terminal domain rich in serine-prolin e clusters and leucines. The human Zf9 gene maps to chromosome POP nea r the telomere. Zf9 binds specifically to a DNA oligonucleotide contai ning a GC box motif, The N-terminal domain of Zf9 (amino acids 1-201) is transactivating in the chimeric GAL4 hybrid system. In Drosophila s chneider cells, full length Zf9 transactivates a reporter construct dr iven by the SV40 promoter/enhancer, which contains several GC boxes. A physiologic role for Zf9 is suggested by its transactivation of a col lagen alpha 1 (I) promoter reporter, Transactivation of collagen alpha 1 (I) by Zf9 is context-dependent, occurring strongly in stellate cel ls, modestly in Hep G2 cells, and not at all in D. schneider cells, Ou r results suggest that Zf9 may be an important signal ire hepatic stel late cell activation after liver injury.