The Gli proteins are the effectors of Hedgehog (Hh) signaling and have been shown to be involved in cell-fate determination, proliferation and patterning in many cell types and most organs during embryo development.
The Gli transcription factors activate/inhibit transcription by binding to Gli responsive genes and by interacting with the transcription complex. The Gli transcription factors have DNA binding zinc finger domains which bind to consensus sequences on their target genes to initiate or suppress transcription. Yoon showed that mutating the Gli zinc finger domain inhibited the proteins effect proving its role as a transcription factor. Gli proteins have an 18-amino acid region highly similar to the α-helical herpes simplex viral protein 16 activation domain. This domain contains a consensus recognition element for the human TFIID TATA box-binding protein associated factor TAFII31. Other proteins such as Missing in Metastasis (MIM/BEG4) have been shown to potentiate the affects of the Gli transcription factors on target gene transcription. Gli and MIM have been shown to act synergistically to induce epidermal growth and MIM + Gli1 overexpressing grafts show similar growth patterns to Shh grafts.
There are three members of the family; Gli1, Gli2 and Gli3 which are all transcription factors mediating the Hh pathway. The GLI1, GLI2, and GLI3 genes encode transcription factors which all contain conserved tandem C2-H2 zinc fingers domains and a consensus histidine/cysteine linker sequence between zinc fingers. This Gli motif is related to those of Kruppel which is a Drosophila segmentation gene of the gap class. In transgenic mice, mutant Gli1 lacking the zinc fingers does not induce Sonic Hedgehog (Shh) targets. The conserved stretch of 9 amino acids connecting the C-terminal histidine of one finger to the N-terminal cysteine of the next. The GLI consensus finger amino acid sequence is [Y/F]JXCX3GCX3[F/Y]X5LX2HX4H[T/S]GEKP The Gli1 and Gli2 protein zinc finger DNA binding domain have been shown to bind to the DNA consensus GLI binding site GACCACCCA
Gli Proteins transcriptional regulation is tissue specific for many targets. For example Gli1 in primary keratinocytes upregulates FOXM1 whereas in mesenchymal C3H10T1/2 cells it has been shown to upregulate platelet-derived growth factor receptor PDGFRa.
Human GLi1 encodes a transcription activator involved in development that is a known oncogene. It has been found that N-terminal regions of Gli1 recruit histone deacetylase complexes via FuSu, which are involved in DNA folding in chromosomes. This may negatively regulate transcription indicating Gli1 could act as transcriptional inhibitor as well as an activator. The human GLI1 promoter region is regulated by a 1.4 kb 5’ region including a 5’ flanking sequence, an untranslated exon and 425bp of the first intron. Numerous proteins such as Sp1, USF1, USF2, and Twist are also involved in Gli1 promoter regulation . During mouse embryo development Gli1 expression can be detected in the gut mesoderm, ventral neural tube, ependymal layer of the spinal cord, forebrain, midbrain, cerebellum, and in sites of endochondral bone formation (Hui et al., 1994; Walterhouse et al., 1993) Wallace, 1999). Some of the downstream gene targets of human Gli1 include regulators of the cell cycle and apoptosis such as cyclin D2 and plakoglobin respectively (Yoon et al., 2002a). Gli1 also upregulates FoxM1 in BCC. Gli1 expression can also mimic Shh expression in certain cell types (Dahmane et al., 1997b)
GLI1 was originally isolated from a glioma tumour and has been found to be up regulated in many tumors including muscle, brain and skin tumors such as Basal cell carcinoma (BCC) (Altaba et al). Shh and the Gli genes are normally expressed in hair follicles and skin tumours expressing Gli1 may arise from hair follicles. The level of Gli1 expression correlates with the tumor grade in bone and soft tissue sarcomas . Transgenic mice and frogs overexpressing Gli1 develop BCC like tumours as well as other hair follicle-derived neoplasias, such as trichoepitheliomas, cylindromas, and trichoblastomas (Dahmane et al., 1997; Nilsson et al., 2000). Expression of Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1. This suggests that overexpressed Gli1 alone is probably sufficient for tumour development (Nilsson et al., 2000). Mutations leading to the expression of Gli1 in basal cells are thus predicted to induce BCC formation (Dahmane et al., 1997a)
^ Kinzler KW,; Bigner SH; Bigner DD; Trent JM; Law ML; O'Brien SJ; Wong AJ; Vogelstein B. (Apr 1987). "Identification of an amplified, highly expressed gene in a human glioma". Science236 (4797): 70-3. PMID 3563490.
^ Ruiz i Altaba A. (Jun 1999). "Gli proteins encode context-dependent positive and negative functions: implications for development and disease.". Development126 (14): 3205-16. PMID 10375510.
^ Sasaki H,; Hui C; Nakafuku M; Kondoh H. (Apr 1997). "A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro". Development124 (7): 1313-22. PMID 9118802.
^ abc Liu CZ; Yang JT; Yoon JW; Villavicencio E; Pfendler K; Walterhouse D; Iannaccone P (Mar 1998). "Characterization of the promoter region and genomic organization of GLI, a member of the Sonic hedgehog-Patched signaling pathway". Gene209 (1-2): 1-11. PMID 9524201.
^ Callahan CA et al. (Nov 2004). "MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription". Genes Dev.18 (22): 2724-9.. PMID 15545630.
^ ab Ruppert JM et al (Aug 1988). "The GLI-Kruppel family of human genes". Mol Cell Biol.8 (8): 3104-13.. PMID 2850480.
^ Park HL et al. (Apr 2000). "Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation". Development127 (8): 1593-605.. PMID 10725236.
^ Kinzler KW; Vogelstein B. (Feb 1990). "The GLI gene encodes a nuclear protein which binds specific sequences in the human genome.". Mol Cell Biol.10 (2): 634-42. PMID 2105456.
^ ab Teh MT; Wong ST; Neill GW; Ghali LR; Philpott MP; Quinn AG (Aug 2002). "FOXM1 is a downstream target of Gli1 in basal cell carcinomas.". Cancer Res.62 (16): 4773-80. PMID 12183437.
Xie J et al. (Jul 2001). "A role of PDGFRalpha in basal cell carcinoma proliferation". Proc Natl Acad Sci U S A.9 (16): 9255-9. PMID 11481486.
^ Kinzler KW et al (Apr 1987). "Identification of an amplified, highly expressed gene in a human glioma.". Science236 (4797): 70-3.. PMID 3563490.
^ Cheng SY; Bishop JM. (Apr 2002). "Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex." 99 (8): 5442-7.. PMID 11960000.
^ Jacob J; Briscoe J. (Aug 2003). "Gli proteins and the control of spinal-cord patterning". EMBO Rep.4 (8): 761-5. PMID 12897799.
^ Villavicencio EH; Yoon JW; Frank DJ; Fuchtbauer EM; Walterhouse DO; Iannaccone PM. (Apr 2002). "Cooperative E-box regulation of human GLI1 by TWIST and USF.". Genesis.32 (4): 247-58.. PMID 11948912.
^ Gitelman I. (Sep 1997). "Twist protein in mouse embryogenesis.". Dev Biol.189 (2): 205-14.
^ Hebrok M; Fuchtbauer A; Fuchtbauer EM. (May 1997). "Repression of muscle-specific gene activation by the murine Twist protein.". Exp Cell Res.232 (2): 295-303.. PMID 9168805.
^ Dahmane N; Lee J; Robins P; Heller P; Ruiz i Altaba A. (Oct 1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.". Nature389 (6653): 876-81. PMID 9349822. “Erratum in: Nature 1997 Dec 4;390(6659):536.”