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Regulation of human protein Z gene expression by liver‐enriched transcription factor HNF‐4α and ubiquitous factor Sp1
Author(s) -
SUGAWARA H.,
IWATA H.,
SOURI M.,
ICHINOSE A.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02738.x
Subject(s) - transcription factor , sp1 transcription factor , cancer research , biology , gene , promoter , gene expression , genetics
Summary. Background and objectives: Protein Z (PZ), which regulates blood coagulation, is mainly synthesized in the liver. Its plasma level varies widely among individuals, and is highly sensitive to Warfarin. The mechanism for the basic transcription of the human PZ gene, however, has not been reported. The aim of this study was to elucidate the mechanism of gene regulation for PZ by characterizing its 5′‐flanking region. Methods and results: A reporter gene assay using the human hepatoma cell line, HepG2, identified a minimal promoter region (site A) and two enhancer regions (sites B and C) in the PZ gene. DNase I footprinting and electromobility shift assays revealed binding of the liver‐enriched transcriptional factor hepatocyte nuclear factor (HNF)‐4α to site A, the ubiquitous transcriptional factor Sp1 to sites A and C, and an unidentified factor to site B. The co‐transfection of an HNF‐4α expression vector with reporter gene constructs to the non‐hepatic cell line HeLa resulted in a significant increase of PZ promoter activity. Conclusions: HNF‐4α plays a crucial role in human PZ gene expression in hepatocytic cells, and Sp1 is also important. These findings provide the first step toward understanding the mechanisms of the varying plasma PZ levels in individuals under physiological and pathological conditions.