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J. Biol. Chem., Vol. 275, Issue 48, 37604-37611, December 1, 2000

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An Alternative, Human SRC Promoter and Its Regulation by Hepatic Nuclear Factor-1^*

Keith Bonham^§, Shawn A. Ritchie^¶, Scott M. Dehm^¶, Kevin Snyder^¶, and F. Mark Boyd

From the  Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency and the Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 4H4, Canada and the ^¶ Department of Biochemistry, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada

The SRC gene encodes the proto-oncogene pp60^c-src, a tyrosine kinase implicated in numerous signal transduction pathways. In addition, the SRC gene is differentially expressed, developmentally regulated, and frequently overexpressed in human neoplasia. However, the mechanisms regulating its expression have not been completely explored. Here we describe the isolation of a new distal SRC promoter and associated exon, designated 1, which we mapped to a position 1.0 kilobase upstream of the previously described SRC1A housekeeping promoter. Differential use of these promoters and their associated exons coupled with subsequent splicing to a common downstream exon results in c-Src transcripts with different 5' ends but identical coding regions. Promoter analysis following transient transfections into HepG2 cells mapped the minimal 1 promoter to a region 145 bp upstream of the major transcription start site. This region contained a consensus binding site for hepatic nuclear factor-1 (HNF-1), a liver-enriched transcription factor implicated in the regulation of a number of genes in liver, kidney, stomach, intestine, and pancreas. Subsequent mobility shift assays confirmed that HNF-1 isoform was the predominant factor interacting with this region of the promoter. Mutation of the HNF-1 site resulted in a dramatic reduction in SRC promoter activity. Cotransfection studies demonstrated the promoter could be strongly transactivated by the HNF-1 isoform but not by the related HNF-1 factor. Consistent with these results, we demonstrated that transcripts originating from the SRC1 promoter display a tissue restricted pattern of expression with highest levels present in stomach, kidney, and pancreas. These results indicate that SRC transcriptional regulation is much more complex than previously realized and implicates HNF-1 in both the tissue-specific regulation of the SRC gene in normal tissues and the overexpression of c-Src in certain human cancers.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF272982.

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