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Regulation of Human Nitric Oxide Synthase 2 Expression by Wnt ß-Catenin Signaling

¹ Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania and ² Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: S. Perwez Hussain, Laboratory of Human Carcinogenesis, Building 37, Room 3060D, National Cancer Institute, NIH, Bethesda, MD 20892-4255. Phone: 301-402-3431; Fax: 301-496-0497; E-mail: hussainp{at}mail.nih.gov or David A. Geller, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213. Phone: 412-692-2001; E-mail: gellerda{at}upmc.edu.

Nitric oxide (NO·), an important mediator of inflammation, and ß-catenin, a component of the Wnt–adenomatous polyposis coli signaling pathway, contribute to the development of cancer. We have identified two T-cell factor 4 (Tcf-4)-binding elements (TBE1 and TBE2) in the promoter of human inducible NO synthase 2 (NOS2). We tested the hypothesis that ß-catenin regulates human NOS2 gene. Mutation in either of the two TBE sites decreased the basal and cytokine-induced NOS2 promoter activity in different cell lines. The promoter activity was significantly reduced when both TBE1 and TBE2 sites were mutated (P < 0.01). Nuclear extract from HCT116, HepG2, or DLD1 cells bound to NOS2 TBE1 or TBE2 oligonucleotides in electrophoretic mobility shift assays and the specific protein-DNA complexes were supershifted with anti-ß-catenin or anti-Tcf-4 antibody. Overexpression of ß-catenin and Tcf-4 significantly increased both basal and cytokine-induced NOS2 promoter activity (P < 0.01), and the induction was dependent on intact TBE sites. Overexpression of ß-catenin or Tcf-4 increased NOS2 mRNA and protein expression in HCT116 cells. Lithium chloride (LiCl), an inhibitor of glycogen synthase kinase-3ß, increased cytosolic and nuclear ß-catenin level, NOS2 expression, and NO· production in primary human and rat hepatocytes and cancer cell lines. Treatment with Wnt-3A-conditioned medium increased ß-catenin and NOS2 expression in fetal human hepatocytes. When administered in vivo, LiCl increased hepatic ß-catenin level in a dose-dependent manner with simultaneous increase in NOS2 expression. These data are consistent with the hypothesis that ß-catenin up-regulates NOS2 and suggest a novel mechanism by which the Wnt/ß-catenin signaling pathway may contribute to cancer by increasing NO· production. (Cancer Res 2006; 66(14): 7024-31)

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