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J Biol Chem, Vol. 275, Issue 2, 847-854, January 14, 2000
From the Saskatoon Cancer Center Research Unit, Saskatchewan Cancer
Agency. Division of Oncology and 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.
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*
, Department of
Biochemistry, University of Saskatchewan, Saskatoon,
Saskatchewan S7N 4H4, Canada
*
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.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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