title: Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells.
abstract: Survivin, an important antiapoptotic protein, is expressed in tumors, whereas in normal tissues the expression of this protein is extremely low, defining a role for survivin as a cancer gene. Survivin exhibits multifunctional activity in tumor cells. However, why survivin expression is sharply and invariably restricted to tumor tissue remains unclear. Here, we identified 11 putative consensus binding sites for GLI transcription factors in the survivin promoter and characterized the promoter activity. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the promoter activity in reporter assays. ΔNGLI2 (which lacks the repressor domain) was the most potent vector in activating the survivin promoter-reporter. Moreover, GANT61, a GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA expression in most cells across a large panel of tumor cell lines. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. The ectopic GLI2-evoked expression of endogenous survivin was observed in normal human fibroblasts. GANT61 decreased survivin level in nude mice tumors, mimicking the activity of GANT61 in cultured cells. The immunohistochemistry and double immunofluorescence of human tumors revealed a correlation between the tissue regions showing high GLI2 and survivin positivity. Thus, these results demonstrated that survivin is a classical transcriptional target of GLI2, a Hedgehog pathway signaling effector. This potentially reflects the high expression of survivin in human tumor cells. As the Hedgehog pathway is upregulated in virtually all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors as a potential target for the development of a more effective treatment of cancers through the inhibition of GLI2 to restrain survivin activity.
authors.affiliation: Laboratory of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Vlčková
authors.affiliation: Laboratory of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Ondrušová
authors.affiliation: Laboratory of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Vachtenheim
authors.affiliation: Laboratory of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Réda
authors.affiliation: Institute of Pathology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Dundr
authors.affiliation: Institute of Biophysics and Informatics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Zadinová
authors.affiliation: Laboratory of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Žáková
authors.affiliation: Institute of Biophysics and Informatics, Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Poučková
mesh_terms: D000818:Animals; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D014162:Transfection
chemical_list: C117749:Birc5 protein, mouse; D053823:Hedgehog Proteins; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin