GLI1

Gli1 is a protein originally isolated in human glioblastoma [cite journal
journal=Science
year=1987
month=Apr
volume=236
issue=4797
pages=70–3
title=Identification of an amplified, highly expressed gene in a human glioma
author=Kinzler KW,
coauthors=Bigner SH; Bigner DD; Trent JM; Law ML; O'Brien SJ; Wong AJ; Vogelstein B.
pmid=3563490
doi=10.1126/science.3563490 ] .

Overview

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 [cite journal
journal=Development
year=1999
month=Jun
volume=126
issue=14
pages=3205–16
title=Gli proteins encode context-dependent positive and negative functions: implications for development and disease.
author=Ruiz i Altaba A.
pmid=10375510] . 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 [cite journal
journal=Development
year=1997
month=Apr
volume=124
issue=7
pages=1313–22
title=A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro
author=Sasaki H,
coauthors=Hui C; Nakafuku M; Kondoh H.
pmid=9118802 ] . Yooncite journal
author=Liu CZ
coauthors=Yang JT; Yoon JW; Villavicencio E; Pfendler K; Walterhouse D; Iannaccone P
title=Characterization of the promoter region and genomic organization of GLI, a member of the Sonic hedgehog-Patched signaling pathway
journal=Gene
year=1998
month=Mar
volume=209
issue=1-2
pages=1–11
pmid=9524201
doi=10.1016/S0378-1119(97)00668-9 ] 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 [cite journal
author=Callahan CA et al.
title=MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription
journal=Genes Dev.
year=2004
month=Nov
volume=18
issue=22
pages=2724–9.
pmid=15545630
doi=10.1101/gad.1221804] .

Gli Family

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 classcite journal
author=Ruppert JM et al
title=The GLI-Kruppel family of human genes
journal=Mol Cell Biol.
year=1988
month=Aug
volume=8
issue=8
pages=3104–13.
pmid=2850480] . In transgenic mice, mutant Gli1 lacking the zinc fingers does not induce Sonic Hedgehog (Shh) targets [cite journal
author=Park HL et al.
title=Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation
journal=Development
year=2000
month= Apr
volume=127
issue=8
pages=1593–605.
pmid=10725236] . 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 [cite journal
author=Kinzler KW
coauthors=Vogelstein B.
title=The GLI gene encodes a nuclear protein which binds specific sequences in the human genome.
journal=Mol Cell Biol.
year=1990
month=Feb
volume=10
issue=2
pages=634–42
pmid=2105456] Gli Proteins transcriptional regulation is tissue specific for many targets. For example Gli1 in primary keratinocytes upregulates FOXM1cite journal
journal=Cancer Res.
year=2002
month=Aug
volume=62
issue=16
pages=4773–80
title=FOXM1 is a downstream target of Gli1 in basal cell carcinomas.
author=Teh MT
coauthors=Wong ST; Neill GW; Ghali LR; Philpott MP; Quinn AG
pmid=12183437] whereas in mesenchymal C3H10T1/2 cells it has been shown to upregulate platelet-derived growth factor receptor PDGFRa [cite journal
author=Xie J et al.
title=A role of PDGFRalpha in basal cell carcinoma proliferation
journal=Proc Natl Acad Sci U S A.
year=2001
month=Jul
volume=9
issue=16
pages=9255–9
pmid=11481486
doi=10.1073/pnas.151173398] .

Human GLi1 encodes a transcription activator involved in development that is a known oncogene [cite journal
author=Kinzler KW et al
title=Identification of an amplified, highly expressed gene in a human glioma.
journal=Science
year=1987
month=Apr
volume=236
issue=4797
pages=70–3.
pmid=3563490
doi=10.1126/science.3563490 ] . It has been found that N-terminal regions of Gli1 recruit histone deacetylase complexes via FuSu, which are involved in DNA folding in chromosomes [cite journal
author=Cheng SY
coauthors=Bishop JM.
title=Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex.
jouranl=Proc Natl Acad Sci U S A.
year=2002
month=Apr
volume=99
issue=8
pages=5442–7.
pmid=11960000] . This may negatively regulate transcription indicating Gli1 could act as transcriptional inhibitor as well as an activator [cite journal
author=Jacob J
coauthors=Briscoe J.
title=Gli proteins and the control of spinal-cord patterning
journal=EMBO Rep.
year=2003
month=Aug
volume=4
issue=8
pages=761–5
pmid=12897799
doi=10.1038/sj.embor.embor896 ] . 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 [cite journal
author=Villavicencio EH
coauthors=Yoon JW; Frank DJ; Fuchtbauer EM; Walterhouse DO; Iannaccone PM.
title=Cooperative E-box regulation of human GLI1 by TWIST and USF.
journal=Genesis.
year=2002
month=Apr
volume=32
issue=4
pages=247–58.
pmid=11948912
doi=10.1002/gene.10078] [cite journal
author=Gitelman I.
title=Twist protein in mouse embryogenesis.
journal=Dev Biol.
year=1997
month=Sep
volume=189
issue=2
pages=205–14.pmid=9299114
doi=10.1006/dbio.1997.8614 ] [cite journal
author=Hebrok M
coauthors=Fuchtbauer A; Fuchtbauer EM.
title=Repression of muscle-specific gene activation by the murine Twist protein.
journal=Exp Cell Res.
year=1997
month=May
volume=232
issue=2
pages=295–303.
pmid=9168805
doi=10.1006/excr.1997.3541] . 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)

Isolation

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 [cite journal
author=Dahmane N
coauthors=Lee J; Robins P; Heller P; Ruiz i Altaba A.
title=Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.
journal=Nature
year=1997
month=Oct
volume=389
issue=6653
pages=876–81
quote=Erratum in: Nature 1997 Dec 4;390(6659):536.
pmid=9349822
doi=10.1038/39918 ] . 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)

References

External links

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