GLI2

Last updated
GLI2
Identifiers
Aliases GLI2 , CJS, HPE9, PHS2, THP1, THP2, GLI family zinc finger 2
External IDs OMIM: 165230; MGI: 95728; HomoloGene: 12725; GeneCards: GLI2; OMA:GLI2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2736

14633

Ensembl

ENSG00000074047

ENSMUSG00000048402

UniProt

P10070

Q0VGT2

RefSeq (mRNA)

NM_001081125

RefSeq (protein)

NP_005261
NP_001358200
NP_001361282
NP_001361283

NP_001074594

Location (UCSC) Chr 2: 120.74 – 120.99 Mb Chr 1: 118.76 – 118.98 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. [5] The protein encoded by this gene is a transcription factor. [6]

Contents

GLI2 belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. [7]

Isoforms

There are four isoforms: Gli2 alpha, beta, gamma and delta. [8]

Structure

C-terminal activator and N-terminal repressor regions have been identified in both Gli2 and Gli3. [9] 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, Brachyury genes involved in tissue specification and Xhox3 genes involved in positional information. [10] 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. [11] Additionally, in the amphibian model organism Xenopus laevis, it has been shown that Gli2 plays a key role in the induction, specification, migration and differentiation of the neural crest. [12] In this context, Gli2 is responding to the Indian Hedgehog signaling pathway. [13]

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. [11] Gli2 and Gli3 are important in the formation and development of lung, trachea and oesophagus tissue during embryo development. [14] Studies have also shown that GLI2 plays a dual role as activator of keratinocyte proliferation and repressor of epidermal differentiation. [15] 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. [14] 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. [16] 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. [17] Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level. [14] [18] [19] 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. [20]

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. [21] Gli2 is expressed in the interfollicular 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. [22]

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. [8]

Clinical significance

Mutations of the GLI2 gene are associated with midline craniofacial anomalies, hypopituitarism, and sometimes holoprosencephaly (https://omim.org/entry/165230, Holoprosencephaly 9, Culler-Jones syndrome) [7]

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. [15]

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.

Cis-regulatory catalog of GLI2

Minhas et al. 2015 have recently elucidated a subset of cis-regulatory elements controlling GLI2 expression. They have shown that conserved non-coding elements (CNEs) from the intron of GLI2 gene act as tissue-specific enhancers and reporter gene expression induced by these elements correlates with previously reported endogenous gli2 expression in zebrafish. The regulatory activities of these elements are observed in several embryonic domains, including neural tube and pectoral fin. [23]

Related Research Articles

<span class="mw-page-title-main">Neural tube</span> Developmental precursor to the central nervous system

In the developing chordate, the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, and ultimately the folds meet and coalesce in the middle line and convert the groove into the closed neural tube. In humans, neural tube closure usually occurs by the fourth week of pregnancy.

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.

In the vertebrate embryo, a rhombomere is a transiently divided segment of the developing neural tube, within the hindbrain region in the area that will eventually become the rhombencephalon. The rhombomeres appear as a series of slightly constricted swellings in the neural tube, caudal to the cephalic flexure. In human embryonic development, the rhombomeres are present by day 29.

<span class="mw-page-title-main">Morphogen</span> Biological substance that guides development by non-uniform distribution

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

<span class="mw-page-title-main">GLI1</span> Protein-coding gene in humans

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.

<span class="mw-page-title-main">GLI3</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.

<span class="mw-page-title-main">PAX3</span> Paired box gene 3

The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.

<span class="mw-page-title-main">Floor plate</span> Embryonic structure

The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis from the midbrain to the tail regions. It has been shown that the floor plate is conserved among vertebrates, such as zebrafish and mice, with homologous structures in invertebrates such as the fruit fly Drosophila and the nematode C. elegans. Functionally, the structure serves as an organizer to ventralize tissues in the embryo as well as to guide neuronal positioning and differentiation along the dorsoventral axis of the neural tube.

<span class="mw-page-title-main">Limb development</span>

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

Gremlin is an inhibitor in the TGF beta signaling pathway. It primarily inhibits bone morphogenesis and is implicated in disorders of increased bone formation and several cancers.

<span class="mw-page-title-main">PLAGL1</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein PLAGL1 is a protein that in humans is encoded by the PLAGL1 gene.

<span class="mw-page-title-main">FOXM1</span> Protein-coding gene in humans

Forkhead box protein M1 is a protein that in humans is encoded by the FOXM1 gene. The protein encoded by this gene is a member of the FOX family of transcription factors. Its potential as a target for future cancer treatments led to it being designated the 2010 Molecule of the Year.

<span class="mw-page-title-main">STIL</span> Protein-coding gene in the species Homo sapiens

SCL-interrupting locus protein is a protein that in humans is encoded by the STIL gene. STIL is present in many different cell types and is essential for centriole biogenesis. This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint.

<span class="mw-page-title-main">SUFU</span> Protein-coding gene in the species Homo sapiens

Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene. In molecular biology, the protein domain suppressor of fused protein (Sufu) has an important role in the cell. The Sufu is important in negatively regulating an important signalling pathway in the cell, the Hedgehog signalling pathway (HH). This particular pathway is crucial in embryonic development. There are several homologues of Sufu, found in a wide variety of organisms.

<span class="mw-page-title-main">ZIC2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein ZIC2 is a protein that in humans is encoded by the ZIC2 gene. ZIC2 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

<span class="mw-page-title-main">CDON</span> Protein-coding gene in the species Homo sapiens

Cell adhesion molecule-related/down-regulated by oncogenes is a protein that in humans is encoded by the CDON gene.

<span class="mw-page-title-main">Zone of polarizing activity</span>

The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the ZPA, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn't until 1993 that Todt and Fallon showed that the AER and ZPA are dependent on each other.

<span class="mw-page-title-main">GLIS1</span> Protein-coding gene

Glis1 is gene encoding a Krüppel-like protein of the same name whose locus is found on Chromosome 1p32.3. The gene is enriched in unfertilised eggs and embryos at the one cell stage and it can be used to promote direct reprogramming of somatic cells to induced pluripotent stem cells, also known as iPS cells. Glis1 is a highly promiscuous transcription factor, regulating the expression of numerous genes, either positively or negatively. In organisms, Glis1 does not appear to have any directly important functions. Mice whose Glis1 gene has been removed have no noticeable change to their phenotype.

Hedgehog pathway inhibitors, also sometimes called hedgehog inhibitors, are small molecules that inhibit the activity of a component of the Hedgehog signaling pathway. Due to the role of aberrant Hedgehog signaling in tumor progression and cancer stem cell maintenance across cancer types, inhibition of the Hedgehog signaling pathway can be a useful strategy for restricting tumor growth and for preventing the recurrence of the disease post-surgery, post-radiotherapy, or post-chemotherapy. Thus, Hedgehog pathway inhibitors are an important class of anti-cancer drugs. At least three Hedgehog pathway inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment. These include vismodegib and sonidegib, both inhibitors of Smoothened (SMO), which are being used for the treatment of basal cell carcinoma. Arsenic trioxide, an inhibitor of GLI transcription factors, is being used for the treatment of acute promyelocytic leukemia. In addition, multiple other Hedgehog pathway inhibitors are in different phases of clinical trials.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000074047 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000048402 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Tanimura A, Dan S, Yoshida M (May 1998). "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 of Virology. 72 (5): 3958–64. doi:10.1128/JVI.72.5.3958-3964.1998. PMC   109622 . PMID   9557682.
  6. ↑ Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML, Seuanez HN, O'Brien SJ, Vogelstein B (August 1988). "The GLI-Kruppel family of human genes". Molecular and Cellular Biology. 8 (8): 3104–13. doi:10.1128/mcb.8.8.3104. PMC   363537 . PMID   2850480.
  7. 1 2 "Entrez Gene: GLI family zinc finger 2".
  8. 1 2 Tojo M, Kiyosawa H, Iwatsuki K, Nakamura K, Kaneko F (May 2003). "Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma". The British Journal of Dermatology. 148 (5): 892–7. doi:10.1046/j.1365-2133.2003.05284.x. PMID   12786818. S2CID   23655947.
  9. ↑ Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (September 1999). "Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling". Development. 126 (17): 3915–24. doi:10.1242/dev.126.17.3915. PMID   10433919.
  10. ↑ Brewster R, Mullor JL, Ruiz i Altaba A (October 2000). "Gli2 functions in FGF signaling during antero-posterior patterning". Development. 127 (20): 4395–405. doi:10.1242/dev.127.20.4395. PMID   11003839.
  11. 1 2 Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, Esterbauer H, Hauser-Kronberger C, Frischauf AM, Aberger F (November 2004). "Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2". Cancer Research. 64 (21): 7724–31. doi: 10.1158/0008-5472.CAN-04-1085 . PMID   15520176.
  12. ↑ Cerrizuela S, Vega-López GA, Palacio MB, Tríbulo C, Aybar MJ (August 2018). "Gli2 is required for the induction and migration of Xenopus laevis neural crest". Mechanisms of Development. 154: 219–239. doi: 10.1016/j.mod.2018.07.010 . hdl: 11336/101714 . PMID   30086335.
  13. ↑ Agüero TH, Fernández JP, López GA, Tríbulo C, Aybar MJ (April 2012). "Indian hedgehog signaling is required for proper formation, maintenance and migration of Xenopus neural crest". Developmental Biology. 364 (2): 99–113. doi: 10.1016/j.ydbio.2012.01.020 . hdl: 11336/60718 . PMID   22309705.
  14. 1 2 3 Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC (September 1998). "Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus". Nature Genetics. 20 (1): 54–7. doi:10.1038/1711. PMID   9731531. S2CID   195211836.
  15. 1 2 Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Ikram MS, Quinn AG, Philpott MP, Frischauf AM, Aberger F (February 2004). "The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells". Oncogene. 23 (6): 1263–74. doi:10.1038/sj.onc.1207240. PMID   14691458. S2CID   23702873.
  16. ↑ Litingtung Y, Chiang C (October 2000). "Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3". Nature Neuroscience. 3 (10): 979–85. doi:10.1038/79916. PMID   11017169. S2CID   10102370.
  17. ↑ Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL (April 2000). "Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation". Development. 127 (8): 1593–605. doi:10.1242/dev.127.8.1593. PMID   10725236.
  18. ↑ Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH, Joyner AL, Hui C (January 1997). "Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development". Development. 124 (1): 113–23. doi:10.1242/dev.124.1.113. PMID   9006072.
  19. ↑ Hardcastle Z, Mo R, Hui CC, Sharpe PT (August 1998). "The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants". Development. 125 (15): 2803–11. doi:10.1242/dev.125.15.2803. PMID   9655803.
  20. ↑ Yang JT, Liu CZ, Villavicencio EH, Yoon JW, Walterhouse D, Iannaccone PM (December 1997). "Expression of human GLI in mice results in failure to thrive, early death, and patchy Hirschsprung-like gastrointestinal dilatation". Molecular Medicine. 3 (12): 826–35. doi:10.1007/bf03401719. PMC   2230283 . PMID   9440116.
  21. ↑ Sheng H, Goich S, Wang A, Grachtchouk M, Lowe L, Mo R, Lin K, de Sauvage FJ, Sasaki H, Hui CC, Dlugosz AA (September 2002). "Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype". Cancer Research. 62 (18): 5308–16. PMID   12235001.
  22. ↑ Oro AE, Higgins K (March 2003). "Hair cycle regulation of Hedgehog signal reception". Developmental Biology. 255 (2): 238–48. doi:10.1016/S0012-1606(02)00042-8. PMID   12648487.
  23. ↑ Minhas R, Pauls S, Ali S, Doglio L, Khan MR, Elgar G, Abbasi AA (May 2015). "Cis-regulatory control of human GLI2 expression in the developing neural tube and limb bud". Developmental Dynamics. 244 (5): 681–92. doi:10.1002/dvdy.24266. PMID   25715918. S2CID   6566275.

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