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J Biol Chem, Vol. 275, Issue 2, 847-854, January 14, 2000

Transcription of the Human c-Src Promoter Is Dependent on Sp1, a Novel Pyrimidine Binding Factor SPy, and Can Be Inhibited by Triplex-forming Oligonucleotides*

Shawn RitchieDagger , F. Mark Boyd, Jason Wong, and Keith Bonham§

From the Saskatoon Cancer Center Research Unit, Saskatchewan Cancer Agency. Division of Oncology and Dagger  Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada

The tyrosine kinase pp60c-src has been implicated in the regulation of numerous normal physiological processes as well the development of several human cancers. However, the mechanisms regulating its expression have not been addressed. In the present study, we report the presence of two Sp1/Sp3 binding sites and three polypurine:polypyrimidine (Pu:Py) tracts in the c-Src promoter that are essential for controlling expression. We demonstrate that Sp1, but not Sp3, is capable of activating the c-Src promoter and that Sp3 is also capable of inhibiting Sp1-mediated transactivation. The presence of multiple Pu:Py tracts conferred S1 sensitivity on plasmids in vitro, suggesting they are capable of adopting non B-DNA conformations. These tracts specifically bind a nuclear factor we named SPy (Src pyrimidine binding factor), which demonstrates both novel double- and single-stranded binding specificities. Mutations eliminating SPy binding compromised Src transcriptional activity, especially in concert with additional mutations affecting Sp1 binding, suggesting the two factors may cooperate in regulating c-Src expression. Finally, we demonstrate that triplex-forming oligonucleotides designed to target both Sp1 and SPy binding sites can down-regulate c-Src expression in vitro, suggesting a potential therapeutic approach to controlling c-Src expression in diseases where aberrant expression or activity has been documented.

* This work was supported by grants from the Medical Research Council of Canada (to K. B.), the Health Services Utilization Research Commission, Saskatchewan, and the University of Saskatchewan College of Medicine scholarship program (to S. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Saskatoon Cancer Center Research Unit, Saskatchewan Cancer Agency, Div. of Oncology, University of Saskatchewan, 20 Campus Dr., Saskatoon, Saskatchewan S7N 4H4, Canada. Tel.: 306-655-2313; Fax: 306-655-2910; E-mail: kbonham@scf.sk.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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