title: GLI2 cell-specific activity is controlled at the level of transcription and RNA processing: Consequences to cancer metastasis.
abstract: High activity of GLI family zinc finger protein 2 (GLI2) promotes tumor progression. Removal of the repressor domain at the N terminus (GLI2∆N) by recombinant methods converts GLI2 into a powerful transcriptional activator. However, molecular mechanisms leading to the formation of GLI2∆N activator proteins have not been established. Herein we report for the first time that the functional activities of GLI2 are parted into different protein isoforms by alternative promoter usage, selection of alternative splicing, transcription initiation and termination sites. Functional studies using melanoma cells revealed that transcriptional regulation of GLI2 is TGFbeta-dependent and supports the predominant production of GLI2∆N and C-terminally truncated GLI2 (GLI2∆C) isoforms in cells with high migratory and invasive phenotype. Taken together, these results highlight the role of transcription and RNA processing as major processes in the regulation of GLI2 activity with severe impacts in cancer development.
authors.affiliation: Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia; Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia.
authors.forename: Helle
authors.initials: H
authors.lastname: Sadam
authors.affiliation: Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia.
authors.forename: Urmas
authors.initials: U
authors.lastname: Liivas
authors.affiliation: Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia; Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia.
authors.forename: Anna
authors.initials: A
authors.lastname: Kazantseva
authors.affiliation: Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia.
authors.forename: Priit
authors.initials: P
authors.lastname: Pruunsild
authors.affiliation: Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia.
authors.forename: Jekaterina
authors.initials: J
authors.lastname: Kazantseva
authors.affiliation: Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia.
authors.forename: Tõnis
authors.initials: T
authors.lastname: Timmusk
authors.affiliation: Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia.
authors.forename: Toomas
authors.initials: T
authors.lastname: Neuman
authors.affiliation: Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia; Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia. Electronic address: kaia@protobios.com.
authors.forename: Kaia
authors.initials: K
authors.lastname: Palm
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C082593:GLI2 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D000075746:Zinc Finger Protein Gli2; D012313:RNA
keywords: Alternative splicing; Cancer; GLI2; Invasion; RNA processing