Cloning of the human GLI2 Promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation.
GLI2 (GLI-Kruppel family member 2), a zinc finger transcription factor that mediates Hedgehog signaling, is implicated in the progression of an ever-growing number of human malignancies, including prostate and pancreatic cancer, as well as basal cell carcinoma of the skin. Its expression is up-regulated by transforming growth factor-beta (TGF-beta) in a variety of cell types, both normal and transformed. We report herein that TGF-beta-driven GLI2 expression is transcriptional and does not result from stabilization of GLI2 transcripts. We describe the characterization of the 5'-flanking sequence of human GLI2 mRNA, the identification of a transcription start site, the cloning of approximately 1,600 bp of the regulatory promoter region and the identification and functional analysis of a TGF-beta-responsive region mapped to a 91-bp sequence between nucleotides -119 and -29 of the promoter. This region harbors SMAD and lymphoid enhancer factor/T cell factor binding sites that allow functional cooperation between SMAD3 and beta-catenin, recruited to the promoter in response to TGF-beta to drive GLI2 gene transcription.
INSERM, U697, Université Paris-Diderot, 75010 Paris, France.
Sylviane
S
Dennler
Jocelyne
J
André
Franck
F
Verrecchia
Alain
A
Mauviel
D001483:Base Sequence; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin; D008156:Luciferases