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 stellate cells activated in vivo. Zf9 expression and biosynthesis are increased markedly in activated cells in vivo compared with cells from normal rats ("quiescent" cells). The factor is localized to the nucleus 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 Kruppel-like family with a unique N-terminal domain rich in serine-proline clusters and leucines. The human zf9 gene maps to chromosome 10P near the telomere. Zf9 binds specifically to a DNA oligonucleotide containing a GC box motif. The N-terminal domain of Zf9 (amino acids 1-201) is transactivating in the chimeric GAL4 hybrid system. In Drosophila schneider cells, full length Zf9 transactivates a reporter construct driven by the SV40 promoter/enhancer, which contains several GC boxes. A physiologic role for Zf9 is suggested by its transactivation of a collagen alpha1(I) promoter reporter. Transactivation of collagen alpha1(I) by Zf9 is context-dependent, occurring strongly in stellate cells, modestly in Hep G2 cells, and not at all in D. schneider cells. Our results suggest that Zf9 may be an important signal in hepatic stellate cell activation after liver injury.
University of California, San Francisco, CA 94143, USA.
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Ratziu
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Lalazar
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Wong
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Dang
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Collins
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Shaulian
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Jensen
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Friedman
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002846:Chromatography, Affinity / Q000379:methods; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008103:Liver Cirrhosis / Q000235:genetics*; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D015854:Up-Regulation
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C105465:KLF6 protein, human; C491357:Klf6 protein, rat; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors