GLI2

protein
Name=GLI-Kruppel family member GLI2
caption=


width=
HGNCid=4318
Symbol=GLI2
AltSymbols=
EntrezGene=2736
OMIM=165230
RefSeq=NM_005270
UniProt=P10070
PDB=
ECnumber=
Chromosome=2
Arm=q
Band=14
LocusSupplementaryData=

GLI-Kruppel family member GLI2 also known as Gli2 is a human gene.cite journal | author = Tanimura A, Dan S, Yoshida M | title = Cloning of novel isoforms of the human Gli2 oncogene and their activities to enhance tax-dependent transcription of the human T-cell leukemia virus type 1 genome | journal = J. Virol. | volume = 72 | issue = 5 | pages = 3958–64 | year = 1998 | month = May | pmid = 9557682 | pmc = 109622 | url = http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=9557682 | issn = ] The protein encoded by this gene is a transcription factor.cite journal | author = Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML, Seuanez HN, O'Brien SJ, Vogelstein | title = The GLI-Kruppel family of human genes | journal = Mol. Cell. Biol. | volume = 8 | issue = 8 | pages = 3104–13 | year = 1988 | month = August | pmid = 2850480 | pmc = 363537 | doi = | url = http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=2850480 | issn = ]

Isoforms

There are four isoforms: Gli2 alpha, beta, gamma and delta.cite journal | author = Tojo M, Kiyosawa H, Iwatsuki K, Nakamura K, Kaneko F | title = Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma | journal = Br. J. Dermatol. | volume = 148 | issue = 5 | pages = 892–7 | year = 2003 | pmid = 12786818 | doi = | issn = ]

tructure

C-terminal activator and N-terminal repressor regions have been identified in both Gli2 and Gli3.cite journal | author = Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H | title = Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling | journal = Development | volume = 126 | issue = 17 | pages = 3915–24 | year = 1999 | pmid = 10433919 | doi = | issn = ] However, the N-terminal part of human Gli2 is much smaller than its mouse or frog homologs, suggesting that it may lack repressor function.

Function

Gli2 affects ventroposterior mesodermal development by regulating at least three different genes; Wnt genes involved in morphogenesis, Brachyruy genes involved in tissue specification and Xhox3 genes involved in positional information.cite journal | author = Brewster R, Mullor JL, Ruiz i Altaba A | title = Gli2 functions in FGF signaling during antero-posterior patterning | journal = Development | volume = 127 | issue = 20 | pages = 4395–405 | year = 2000 | pmid = 11003839 | doi = | url = http://dev.biologists.org/cgi/content/abstract/127/20/4395 | issn = ] The anti-apoptotic protein BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1 – but not Gli3, which may lead to carcinogenesis.cite journal | author = Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, Esterbauer H, Hauser-Kronberger C, Frischauf AM, Aberger F
title = Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2 | journal = Cancer Res. | volume = 64 | issue = 21 | pages = 7724–31 | year = 2004 | pmid = 15520176 | doi = 10.1158/0008-5472.CAN-04-1085 | issn = ]

It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus. This suggests that in mouse embryogenesis, Gli1 and Gli2 regulate a similar set of target genes. Mutations do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent. Gli2 and Gli3 are important in the formation and development of lung, trachea and oesophagus tissue during embryo development.cite journal | author = Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC | title = Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus | journal = Nat. Genet. | volume = 20 | issue = 1 | pages = 54–7 | year = 1998 | pmid = 9731531 | doi = 10.1038/1711 | issn = ] Studies have also shown that GLI2 plays a dual role as activator of keratinocyte proliferation and repressor of
epidermal differentiation.cite journal | author = Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Ikram MS, Quinn AG, Philpott MP, Frischauf AM, Aberger F | title = The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells | journal = Oncogene | volume = 23 | issue = 6 | pages = 1263–74 | year = 2004 | pmid = 14691458 | doi = 10.1038/sj.onc.1207240 | issn = ] There is a significant level of crosstalk and functional overlap between the Gli TFs. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically normal.cite journal | author = Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC | title = Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus | journal = Nat. Genet. | volume = 20 | issue = 1 | pages = 54–7 | year = 1998 | pmid =9731531 | doi= 10.1038/1711 | issn = ] However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally and Gli3 dorsally in transgenic mice.cite journal | author = Litingtung Y, Chiang C | title = Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3 | journal = Nat. Neurosci. | volume = 3 | issue = 10 | pages = 979–85 | year = 2000 | pmid = 11017169 | doi = 10.1038/79916 | issn = ] Gli2 null mice embryos develop neural tube defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Gli1 has been shown to induce the two GLI2 α/β isoforms.

Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs.cite journal | author = 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 | year = 2000 | pmid = 10725236 | doi = | issn = ] Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level.cite journal | author = Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH, Joyner AL, Hui C | title = Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development | journal =Development | volume = 124 | issue = 1 | pages = 113–23 | year = 1997 | pmid = 9006072 | doi = | issn = | url = http://dev.biologists.org/cgi/content/abstract/124/1/113 ] cite journal | author = Hardcastle Z, Mo R, Hui CC, Sharpe PT | title = The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants | journal = Development | volume = 125 | issue = 15 | pages = 2803–11 | year = 1998 | pmid = 9655803 | doi = | issn = | url = http://dev.biologists.org/cgi/content/abstract/125/15/2803 ] cite journal | author = Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC | title = Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus | journal = Nat. Genet. | volume = 20 | issue = 1 | pages = 54–7 | year = 1998 | pmid = 9731531 | doi = 10.1038/1711 | issn = ] These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.

Transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumors form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.cite journal | author = Yang JT, Liu CZ, Villavicencio EH, Yoon JW, Walterhouse D, Iannaccone PM | title = Expression of human GLI in mice results in failure to thrive, early death, and patchy Hirschsprung-like gastrointestinal dilatation | journal = Mol. Med. | volume = 3 | issue = 12 | pages = 826–35 | year = 1997 | pmid = 9440116 | doi = | issn = | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9440116 ]

Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous keratinocytes develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma (BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastomas, cylindromas and hamartomas but rarely developed BCCs.cite journal | author = Sheng H, Goich S, Wang A, Grachtchouk M, Lowe L, Mo R, Lin K, de Sauvage FJ, Sasaki H, Hui CC, Dlugosz AA | title = Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype | journal = Cancer Res. | volume = 62 | issue = 18 | pages = 5308–16 | year = 2002 | pmid = 12235001 | doi = | issn = | url = http://cancerres.aacrjournals.org/cgi/content/abstract/62/18/5308 ] Gli2 is expressed in theinterfollicular epidermis and the outer root sheath of hair follicles in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.cite journal | author = Oro AE, Higgins K | title = Hair cycle regulation of Hedgehog signal reception | journal = Dev. Biol. | volume = 255 | issue = 2 | pages = 238–48 | year = 2003 | pmid = 12648487 | doi = 10.1016/S0012-1606(02)00042-8 | issn = ]

Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.cite journal | author = Tojo M, Kiyosawa H, Iwatsuki K, Nakamura K, Kaneko F | title = Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma | journal = Br. J. Dermatol. | volume = 148 | issue = 5 | pages = 892–7 | year = 2003 | pmid = 12786818 | doi = 10.1046/j.1365-2133.2003.05284.x | issn = ]

In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.cite journal | author = Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Ikram MS, Quinn AG, Philpott MP, Frischauf AM, Aberger F | title = The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells | journal = Oncogene | volume = 23 | issue = 6 | pages = 1263–74 | year = 2004 | pmid = 14691458 | doi = 10.1038/sj.onc.1207240 | issn = ]

Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other.

References

External links

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