A novel splice variant of GLI1 that promotes glioblastoma cell migration and invasion.
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.
Lo
Hui-Wen
HW
Department of Surgery, Duke University, Durham, NC 27710, USA. huiwen.lo@duke.edu
Zhu
Hu
H
Cao
Xinyu
X
Aldrich
Amy
A
Ali-Osman
Francis
F
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
D051927:CD24 Antigen; D003062:Codon; C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
Science. 1987 Apr 3;236(4797):70-3
3563490
Neuro Oncol. 2009 Apr;11(2):101
19237733
Cancer Lett. 2007 Dec 8;258(1):98-108
17950993
Oncogene. 2007 Aug 23;26(39):5752-61
17353902
Oncogene. 2006 Jul 20;25(31):4361-9
16532032
Nat Cell Biol. 1999 Sep;1(5):312-9
10559945
Nat Rev Cancer. 2003 Jul;3(7):489-501
12835669
J Neuropathol Exp Neurol. 1999 Aug;58(8):795-802
10446804
Cancer Cell. 2005 Jun;7(6):575-89
15950906
Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5895-900
17392427
Clin Cancer Res. 2008 Oct 1;14(19):6042-54
18829483
Cancer Res. 2007 Oct 1;67(19):9066-76
17909010
Biochem Biophys Res Commun. 2008 Jan 4;365(1):35-41
17980703
J Biol Chem. 2007 May 11;282(19):14048-55
17353198
Cancer Res. 1990 Nov 1;50(21):6976-80
2208164
Expert Rev Vaccines. 2008 Sep;7(7):977-85
18767947
Mol Cancer Res. 2008 May;6(5):843-50
18505928
Curr Biol. 2007 Jan 23;17(2):165-72
17196391
Mol Cell Biol. 1990 Feb;10(2):634-42
2105456
J Biol Chem. 2007 Jun 22;282(25):18634-18644
17475624
Development. 1997 Apr;124(7):1313-22
9118802
Eur J Cancer. 2006 Mar;42(4):437-45
16406505
Clin Cancer Res. 2003 Oct 15;9(13):4906-13
14581365
Cancer Res. 2005 Dec 1;65(23):10783-93
16322224
Cancer Res. 2009 Feb 15;69(4):1284-92
19190345
Cancer Res. 2006 Feb 15;66(4):1917-22
16488989
J Biol Chem. 2008 May 23;283(21):14345-54
18378682