Cloning of the Human GLI2 Promoter TRANSCRIPTIONAL ACTIVATION BY TRANSFORMING GROWTH FACTOR-β VIA SMAD3/β-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 similar to 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.