View source for GLI1

{{Short description|Protein-coding gene in humans}}
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{{Infobox_gene}}
'''Zinc finger protein GLI1''' also known as '''glioma-associated oncogene''' is a [[protein]] that in humans is encoded by the GLI1 [[gene]].  It was originally isolated from human [[glioblastoma]] cells.<ref>{{cite journal | vauthors= Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B | title = Identification of an amplified, highly expressed gene in a human glioma | journal = Science | volume = 236 | issue = 4797 | pages = 70–3 | date = April 1987 | pmid = 3563490 | doi = 10.1126/science.3563490 | bibcode = 1987Sci...236...70K }}</ref>

== Function ==
The Gli proteins are the effectors of [[Hedgehog signaling pathway|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.<ref>{{cite journal | vauthors= Ruiz i Altaba A | title = Gli proteins encode context-dependent positive and negative functions: implications for development and disease. | journal = Development | volume = 126 | issue = 14 | pages = 3205–16 | date = June 1999 | doi = 10.1242/dev.126.14.3205 | pmid = 10375510 }}</ref> In the developing spinal cord the target genes of Gli proteins, that are themselves transcription factors, are arranged into a complex gene regulatory network that translates the extracellular concentration gradient of [[Sonic hedgehog]] into different cell fates along the dorsoventral axis.<ref name="pmid25398016">{{cite journal |vauthors=Lovrics A, Gao Y, Juhász B, Bock I, Byrne HM, Dinnyés A, Kovács KA |title=Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord |journal=PLOS ONE |volume=9 |issue=11 |pages=11430|date=November 2014 |pmid=25398016 |doi=10.1371/journal.pone.0111430 |pmc=4232242|bibcode=2014PLoSO...9k1430L |doi-access=free }}</ref>

The Gli [[transcription factor]]s 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.<ref>{{cite journal | vauthors= Sasaki H, Hui C, Nakafuku M, Kondoh H | 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 | journal = Development | volume = 124 | issue = 7 | pages = 1313–22 | date = April 1997 | doi = 10.1242/dev.124.7.1313 | pmid = 9118802 }}</ref>  Yoon<ref name="yoon">{{cite journal | vauthors= Liu CZ, 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 | volume = 209 | issue = 1–2 | pages = 1–11 | date = March 1998 | pmid = 9524201 | doi = 10.1016/S0378-1119(97)00668-9 }}</ref> 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.<ref name="yoon"/> Other proteins such as Missing in Metastasis (MIM/BEG4) have been shown to potentiate the effects 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.<ref>{{cite journal | vauthors= Callahan CA, Ofstad T, Horng L, Wang JK, Zhen HH, Coulombe PA, Oro AE | title = MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription | journal = Genes Dev. | volume = 18 | issue = 22 | pages = 2724–9 | date = November 2004 | pmid = 15545630 | pmc = 528890 | doi = 10.1101/gad.1221804 }}
</ref>

==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 finger 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.<ref name="ruppert">{{cite journal | vauthors= Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML, Seuanez HN, O'Brien SJ, Vogelstein B | title = The GLI-Kruppel family of human genes | journal = Mol Cell Biol | volume = 8 | issue = 8 | pages = 3104–13 | date = August 1988 | pmid = 2850480 | pmc = 363537 | doi=10.1128/mcb.8.8.3104| url = http://nsuworks.nova.edu/cgi/viewcontent.cgi?article=1137&context=cnso_bio_facarticles }}</ref> In transgenic mice, mutant Gli1 lacking the zinc fingers does not induce Sonic Hedgehog (Shh) targets.<ref>{{cite journal | vauthors= Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL | title = Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation | journal = Development | volume = 127 | issue = 8 | pages = 1593–605 | date = April 2000 | doi = 10.1242/dev.127.8.1593 | pmid = 10725236 }}</ref> The conserved stretch of 9 amino acids connects 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.<ref name="ruppert"/>  The Gli1 and Gli2 protein zinc finger [[DNA]] binding domain have been shown to bind to the DNA consensus GLI binding site GACCACCCA.
<ref>{{cite journal | vauthors= Kinzler KW, Vogelstein B | title = The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. | journal = Mol Cell Biol | volume = 10 | issue = 2 | pages = 634–42 | date = February 1990 | pmid = 2105456 | pmc = 360861 | doi=10.1128/mcb.10.2.634}}</ref>
 
Gli Proteins transcriptional regulation is tissue specific for many targets.  For example, Gli1 in primary keratinocytes upregulates FOXM1<ref name="Teh_2002">{{cite journal | vauthors= Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG | title = FOXM1 is a downstream target of Gli1 in basal cell carcinomas. | journal = Cancer Res. | volume = 62 | issue = 16 | pages = 4773–80 | date = August 2002 | pmid = 12183437 }}
</ref> whereas in mesenchymal C3H10T1/2 cells it has been shown to upregulate platelet-derived growth factor receptor PDGFRa.<ref>
{{cite journal | vauthors= Xie J, Aszterbaum M, Zhang X, Bonifas JM, Zachary C, Epstein E, McCormick F | title = A role of PDGFRalpha in basal cell carcinoma proliferation | journal = Proc Natl Acad Sci U S A | volume =  98| issue = 16 | pages = 9255–9 | date = July 2001 | pmid = 11481486 | pmc = 55407 | doi = 10.1073/pnas.151173398 | bibcode = 2001PNAS...98.9255X | doi-access = free }}</ref>

Human Gli1 encodes a transcription activator involved in development that is a known [[oncogene]].<ref name="yoon"/><ref>{{cite journal | vauthors= Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B | title = Identification of an amplified, highly expressed gene in a human glioma. | journal = Science | volume = 236 | issue = 4797 | pages = 70–3 | date = April 1987 | pmid = 3563490 | doi = 10.1126/science.3563490 | bibcode = 1987Sci...236...70K }}</ref>  It has been found that N-terminal regions of Gli1 recruit histone deacetylase complexes via SuFu, which are involved in [[DNA]] folding in [[chromosomes]].<ref>{{cite journal | vauthors= Cheng SY, Bishop JM | title = Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. | journal = Proc Natl Acad Sci U S A | volume = 99 | issue = 8 | pages = 5442–7 | date = April 2002 | pmid = 11960000 | pmc = 122788 | doi = 10.1073/pnas.082096999 | bibcode = 2002PNAS...99.5442C | doi-access = free }}</ref>  This may negatively regulate transcription indicating Gli1 could act as transcriptional inhibitor as well as an activator.<ref>{{cite journal | vauthors= Jacob J, Briscoe J | title = Gli proteins and the control of spinal-cord patterning | journal = EMBO Rep. | volume = 4 | issue = 8 | pages = 761–5 | date = August 2003 | pmid = 12897799 | pmc = 1326336 | doi = 10.1038/sj.embor.embor896 }}</ref> 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.<ref>{{cite journal | vauthors= Villavicencio EH, Yoon JW, Frank DJ, Füchtbauer EM, Walterhouse DO, Iannaccone PM | title = Cooperative E-box regulation of human GLI1 by TWIST and USF. | journal = Genesis | volume = 32 | issue = 4 | pages = 247–58 | date = April 2002 | pmid = 11948912 | doi = 10.1002/gene.10078 | s2cid = 12132097 }}</ref><ref>{{cite journal | vauthors= Gitelman I | title = Twist protein in mouse embryogenesis. | journal = Dev. Biol. | volume = 189 | issue = 2 | pages = 205–14 | date = September 1997 | pmid = 9299114 | doi = 10.1006/dbio.1997.8614 | doi-access = free }}</ref><ref>{{cite journal | vauthors= Hebrok M, Füchtbauer A, Füchtbauer EM | title = Repression of muscle-specific gene activation by the murine Twist protein. | journal = Exp. Cell Res. | volume = 232 | issue = 2 | pages = 295–303 | date = May 1997 | pmid = 9168805 | doi = 10.1006/excr.1997.3541 }}</ref>  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.<ref name="Hui_1994">{{cite journal | vauthors = Hui CC, Slusarski D, Platt KA, Holmgren R, Joyner AL | title = Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm- and mesoderm-derived tissues suggests multiple roles during postimplantation development | journal = Dev. Biol. | volume = 162 | issue = 2 | pages = 402–13 | year = 1994  | pmid = 8150204 | doi = 10.1006/dbio.1994.1097 }}</ref><ref name="Walterhouse_1993">{{cite journal | vauthors = Walterhouse D, Ahmed M, Slusarski D, Kalamaras J, Boucher D, Holmgren R, Iannaccone P | title = gli, a zinc finger transcription factor and oncogene, is expressed during normal mouse development | journal = Dev. Dyn. | volume = 196 | issue = 2 | pages = 91–102 | year = 1993 | pmid = 8364225 | doi = 10.1002/aja.1001960203 | s2cid = 8951322 | doi-access = free }}</ref><ref name="Wallace_1999">{{cite journal | vauthors = Wallace VA | title = Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum | journal = Curr. Biol. | volume = 9 | issue = 8 | pages = 445–8 | year = 1999 | pmid = 10226030 | doi = 10.1016/s0960-9822(99)80195-x| s2cid = 12373898 | doi-access = free | bibcode = 1999CBio....9..445W }}</ref>  Some of the downstream gene targets of human Gli1 include regulators of the cell cycle and apoptosis such as cyclin D2 and plakoglobin respectively.<ref name="Yoon_2002">{{cite journal | vauthors = Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone P | title = Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation | journal = J. Biol. Chem. | volume = 277 | issue = 7 | pages = 5548–55 |date=February 2002  | pmid = 11719506 | doi = 10.1074/jbc.M105708200 | doi-access = free }}</ref>   Gli1 also upregulates FoxM1 in BCC.<ref name="Teh_2002"/>  Gli1 expression can also mimic Shh expression in certain cell types.<ref name="Dahmane_1997">{{cite journal | vauthors = Dahmane N, 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 | volume = 389 | issue = 6653 | pages = 876–81 | year = 1997 | pmid = 9349822 | doi = 10.1038/39918 | bibcode = 1997Natur.389..876D | s2cid = 4424572 }}</ref>

==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).<ref name="pmid22114144">{{cite journal | vauthors = Ruiz i Altaba A | title = Hedgehog signaling and the Gli code in stem cells, cancer, and metastases | journal = Sci Signal | volume = 4 | issue = 200 | pages = pt9 | year = 2011 | pmid = 22114144 | doi = 10.1126/scisignal.2002540 }}</ref> 
DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.<ref>{{cite journal | vauthors = Aiello KA, Alter O | title = Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition | journal = PLOS ONE | volume = 11 | issue = 10 | pages = e0164546 | date = October 2016 | pmid = 27798635 | doi = 10.1371/journal.pone.0164546 | pmc=5087864| bibcode = 2016PLoSO..1164546A | doi-access = free }}</ref>
Shh and the Gli genes are normally expressed in [[hair follicle]]s, 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]].<ref>{{cite journal | vauthors= Dahmane N, 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 | volume = 389 | issue = 6653 | pages = 876–81 | date = October 1997 | pmid = 9349822 | doi = 10.1038/39918 | bibcode = 1997Natur.389..876D | s2cid = 4424572 | quote = Erratum in: Nature 1997 December 4;390(6659):536. }}</ref>   [[Transgenic]] mice and frogs overexpressing Gli1 develop BCC like tumours as well as other hair follicle-derived neoplasias, such as trichoepitheliomas, cylindromas, and trichoblastomas.<ref name="Dahmane_1997"/><ref name="Nilsson_2000"/>  Expression of Gli1 in the embryonic frog [[epidermis (skin)|epidermis]] results in the development of [[tumours]] that express endogenous Gli1. This suggests that overexpressed Gli1 alone is probably sufficient for tumour development<ref name="Nilsson_2000">{{cite journal | vauthors = Nilsson M, Undèn AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, Toftgård R | title = Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 7 | pages = 3438–43 | year = 2000 | pmid = 10725363 | pmc = 16258 | doi = 10.1073/pnas.050467397 | doi-access = free }}</ref><ref>{{cite journal | vauthors= Tripathi K, Mani C, Barnett R, Nalluri S, Bachaboina L, Rocconi RP, Athar M, Owen LB, Palle K | title = Gli1 Regulates S-phase Checkpoint in Tumor Cells via Bid and its Inhibition Sensitizes to DNA Topoisomerase 1 Inhibitors. | journal = Journal of Biological Chemistry | date = 2014 | pmid = 25253693 | doi=10.1074/jbc.M114.606483 | volume=289 | issue = 45 | pages=31513–25 | pmc=4223349| doi-access = free }}</ref>  Mutations leading to the expression of Gli1 in [[Stratum basale|basal cell]]s are thus predicted to induce BCC formation.<ref name="Dahmane_1997"/>

==Interactions==
GLI1 has been shown to [[Protein-protein interaction|interact]] with:
* [[SAP18]],<ref name = pmid11960000>{{cite journal | vauthors= Cheng SY, Bishop JM | title = Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 8 | pages = 5442–7 | date = April 2002 | pmid = 11960000 | pmc = 122788 | doi = 10.1073/pnas.082096999 | bibcode = 2002PNAS...99.5442C | doi-access = free }}</ref>
* [[STK36]],<ref name = pmid10806483>{{cite journal | vauthors= Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A, de Sauvage FJ | title = Gli regulation by the opposing activities of fused and suppressor of fused | journal = Nat. Cell Biol. | volume = 2 | issue = 5 | pages = 310–2 | date = May 2000 | pmid = 10806483 | doi = 10.1038/35010610 | s2cid = 31424234 }}</ref> 
* [[SUFU]],<ref name = pmid10564661>{{cite journal | vauthors= Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, de Sauvage FJ, Rosenthal A | title = Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli | journal = J. Cell Sci. | volume = 112 | issue =  23| pages = 4437–48 | date = December 1999 | doi = 10.1242/jcs.112.23.4437 | pmid = 10564661 }}</ref><ref name = pmid10559945>{{cite journal | vauthors= Kogerman P, Grimm T, Kogerman L, Krause D, Undén AB, Sandstedt B, Toftgård R, Zaphiropoulos PG | title = Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1 | journal = Nat. Cell Biol. | volume = 1 | issue = 5 | pages = 312–9 | date = September 1999 | pmid = 10559945 | doi = 10.1038/13031 | s2cid = 6907964 | doi-access = free }}</ref><ref name = pmid12426310>{{cite journal | vauthors= Dunaeva M, Michelson P, Kogerman P, Toftgard R | title = Characterization of the physical interaction of Gli proteins with SUFU proteins | journal = J. Biol. Chem. | volume = 278 | issue = 7 | pages = 5116–22 | date = February 2003 | pmid = 12426310 | doi = 10.1074/jbc.M209492200 | doi-access = free }}</ref>  and
* [[ZIC1]].<ref name = pmid11238441>{{cite journal | vauthors= Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K | title = Physical and functional interactions between Zic and Gli proteins | journal = J. Biol. Chem. | volume = 276 | issue = 10 | pages = 6889–92 | date = March 2001 | pmid = 11238441 | doi = 10.1074/jbc.C000773200 | doi-access = free }}</ref>

== References ==
{{Reflist|2}}

==External links==
* {{MeshName|Gli1+protein}}

{{Transcription factors|g2}}
{{Hedgehog signaling pathway}}

{{PDB_Gallery|geneid=2735}}

{{DEFAULTSORT:Gli1}}
[[Category:Proteins]]
[[Category:Transcription factors]]