title: A novel splice variant of GLI1 that promotes glioblastoma cell migration and invasion.
abstract: The family of GLI zinc finger transcription factors regulates the expression of genes involved in many important cellular processes, notably embryonal development and cellular differentiation. The glioma-associated oncogene homologue 1 (GLI1) isoform, in particular, has attracted much attention because of its frequent activation in many human cancers and its interactions with other signaling pathways, such as those mediated by K-RAS, transforming growth factor-beta, epidermal growth factor receptor, and protein kinase A. Here, we report the identification of a novel truncated GLI1 splice variant, tGLI1, with an in-frame deletion of 123 bases (41 codons) spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Expression of tGLI1 is undetectable in normal cells but is high in glioblastoma multiforme (GBM) and other cancer cells. Although tGLI1 undergoes nuclear translocalization and transactivates GLI1-binding sites similar to GLI1, unlike GLI1, it is associated with increased motility and invasiveness of GBM cells. Using microarray analysis, we showed >100 genes to be differentially expressed in tGLI1-expressing compared with GLI1-expressing GBM cells, although both cell types expressed equal levels of known GLI1-regulated genes, such as PTCH1. We further showed one of the tGLI1 up-regulated genes, CD24, an invasion-associated gene, to be required for the migratory and invasive phenotype of GBM cells. These data provide conclusive evidence for a novel gain-of-function GLI1 splice variant that promotes migration and invasiveness of GBM cells and open up a new research paradigm on the role of the GLI1 pathway in malignancy.
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27710, USA. huiwen.lo@duke.edu
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Lo
authors.forename: Hu
authors.initials: H
authors.lastname: Zhu
authors.forename: Xinyu
authors.initials: X
authors.lastname: Cao
authors.forename: Amy
authors.initials: A
authors.lastname: Aldrich
authors.forename: Francis
authors.initials: F
authors.lastname: Ali-Osman
mesh_terms: D017398:Alternative Splicing; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D003062:Codon; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D051927:CD24 Antigen; D003062:Codon; C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
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