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J. Biol. Chem., Vol. 277, Issue 21, 18510-18516, May 24, 2002

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Cloning and Characterization of the Human Factor XI Gene Promoter
TRANSCRIPTION FACTOR HEPATOCYTE NUCLEAR FACTOR 4 (HNF-4) IS REQUIRED FOR HEPATOCYTE-SPECIFIC EXPRESSION OF FACTOR XI^*

Takashi Tarumi, Dmitri V. Kravtsov, Mingming Zhao, Scott M. Williams, and David Gailani^§

From the Departments of Pathology and Medicine, Vanderbilt University, Nashville, Tennessee 37232-6307 and the  Department of Microbiology, Meharry Medical College, Nashville, Tennessee 37208

Factor XI is the zymogen of a plasma protease produced primarily in liver that is required for normal blood coagulation. We cloned ~2600 base pairs of the human factor XI gene upstream of exon one, identified transcription start sites, and conducted a functional analysis. Luciferase reporter assays demonstrate that the 381 base pairs upstream of exon one are sufficient for maximum promoter activity in HepG2 hepatocellular carcinoma cells. The removal of 19 base pairs between 381 and 363 results in a nearly complete loss of promoter activity. This region contains the sequence ACTTTG, a motif required for binding of the transcription factor hepatocyte nuclear factor 4 (HNF-4) to the promoters of several genes. Gel mobility shift assays using HepG2 or rat hepatocyte nuclear extract confirm HNF-4 binds between bp 375 and 360. Scrambling the ACTTTG motif completely abolishes promoter activity in luciferase assays. The factor XI promoter functions poorly when transfected into HeLa carcinoma cells, and gel mobility shift experiments with HeLa nuclear extracts demonstrate no HNF-4 binding to the ACTTTG sequence. When a rat HNF-4 expression construct is co-transfected into HeLa cells, factor XI promoter activity is enhanced ~10-fold. We conclude that HNF-4 is required for hepatocyte-specific expression of factor XI.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF486577.

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