Dr. Keith Bonham
Dr. Keith Bonham
Senior Research Scientist
Saskatchewan Cancer Agency
Professor, Division of Oncology
Associate Member, Department of Biochemistry
Room 4D30.3 Health Science Building
107 Wiggins Road
University of Saskatchewan
Saskatoon, SK S7N 5E5
My laboratory's chief interest revolves around the structure and control of a human gene called SRC (pronounced SARK). This gene codes for an enzyme which regulates the rate at which a cell divides as well as its ability to move and migrate. If there is too much of the enzyme or it is in an activated state this can contribute to the development of cancer, particularly tumors of the large intestine and breast. We have isolated the complete human gene and have spent the last several years learning what makes SRC tick. To do this we have been studying the genes promoters. Promoters are discrete regions of a gene which act like the volume control on a Hi-Fi regulating the level of SRC produced. Our hope has been to find ways of turning down the volume on the SRC gene. Most lately we have found that a chemical called butyrate (which is a simple natural by-product of bacterial fermentation in the colon) can do exactly this! This provides an exciting link between a colon cancer gene and the food we eat and may help explain how high fiber diets are thought to inhibit the development of bowel cancer. Currently, we are working hard to understand how butyrate and related chemicals are able to control the SRC promoters. Ultimately, this may help us develop new drugs to control SRC levels in tumors such as breast cancer where SRC levels are high. This research is supported by the Canadian Institutes of Health Research and the Saskatchewan Cancer Agency.
B.Sc. (Hons) University of Salford (UK),
Ph.D. University of Calgary
Several projects are currently underway in our laboratory, all concerned in one manner or another with regulation of the human SRC gene. The SRC gene encodes a non-receptor tyrosine kinase, pp60c-src, and is the human homologue of the transforming gene of Rous Sarcoma Virus. c-Src has been linked to a bewildering array of signaling pathways impacting cellular proliferation, transformation, differentiation, survival, adhesion and migration.
Our work stems from the numerous observation over the years that link overexpression and activation of c-Src to the development of various human cancers, especially those of the colon and breast. We recently identified a subset of tumor cell lines that constitutively overexpress c-Src mRNA and protein. Scott Dehm has in turn shown that this results from SRC transcriptional activation. Therefore, unlike most groups working on c-Src, we have concentrated our efforts on understanding the structure and regulation of the SRC gene itself, rather than the gene product. We have isolated the SRC gene and shown that it is regulated by at least two promoters each associated with its own distinct exon. Differential promoter usage and subsequent splicing to a common downstream exon results in SRC transcripts with identical coding capacity but with different 5' noncoding regions. The proximal SRC1A promoter bears many hallmarks of a housekeeping gene including high GC content and multiple start sites. Mark Boyd originally demonstrated that SRC1A is regulated by the Sp1 family of transcription factors while Shawn Ritchie has been studying several long Polypurine:Polypyrimidine tracts (TC1, TC2 and TC3) present in the promoter. Shawn's studies revealed that these tracts contribute significantly to the transcriptional activity of the SRC1A promoter. He also showed that binding of a factor we called SPy (SRC Pyrimidine binding factor) was responsible for this activity. Recently, Shawn purified this SPy factor and identified it as hnRNP-K.
The distal SRC1alpha promoter is located just 1.0kb upstream of the SRC1A promoter. While the SRC1A promoter appears to regulate expression in many tissues, the SRC1alpha promoter is expressed in a much more restricted fashion and is controlled by Hepatic Nuclear Factor (HNF-1). HNF-1 is a homeodomain containing transcription factor regulating various genes in tissues such as intestine and liver. HNF-1 may thus be an important factor in regulating overexpression of SRC in tumors originating in these tissues. A major focus of the lab is now to understand how these two closely linked promoters are differentially regulated in a variety of normal and malignant cells.