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GLI2 (GLI family zinc finger 2)

Written2013-02Nansalmaa Amarsaikhan, Sherine F Elsawa
Department of Biological Sciences, Northern Illinois University, DeKalb, Illinois, United States of America

(Note : for Links provided by Atlas : click)

Identity

Alias_namesGLI-Kruppel family member GLI2
glioma-associated oncogene family zinc finger 2
Alias_symbol (synonym)THP2
HPE9
THP1
Other alias
HGNC (Hugo) GLI2
LocusID (NCBI) 2736
Atlas_Id 40718
Location 2q14.2  [Link to chromosome band 2q14]
Location_base_pair Starts at 120797291 and ends at 120992653 bp from pter ( according to hg19-Feb_2009)  [Mapping GLI2.png]

DNA/RNA

Description The GLI2 gene encodes one of the three zinc finger transcription factors that are involved in Hedgehog signaling. It was identified by using GLI1 cDNA as a probe (Ruppert et. al, 1988). Human GLI2 gene comprises 13 exons (Roessler et al., 2005).

Protein

 
  Figure 1. Schematic representation of GLI functional domains. (Fernandez-Zapico et al., 2008).
Description Protein: Human GLI2 was originally identified as a Tax-helper protein (THP) that binds to Tax-responsive element in the long terminal repeat of the human T-cell leukemia virus (Tanimura et al., 1998). However, when compared to orthologous GLI2 genes from different species, the human mRNAs lacked a part of the 5' region encoding the evolutionarily conserved N-terminus of GLI2. Roessler et al discovered a 5' sequence encoding 328 amino acids and showed that this previously undescribed amino-terminal repressor domain was essential for the dominant negative activity of the human GLI2 (Roessler et al., 2005). Thus, the full length GLI2 contains 1586 amino acids and in vitro transcriptional activity of the full length GLI2 is about 30 fold lower than the N-delta GLI2, previously known as GLI2 (Roessler et al., 2005). The predicted molecular weight of the full length GLI2 is 197 kDa.
GLI2 promoter: The promoter region of GLI2 has been cloned and defined by Dennler et al. (Dennler et al., 2007). 5'-RACE was used to identify the transcription start site and the promoter sequence was defined to be about 1600-bp upstream of the transcription initiation site (Dennler et al., 2007).
Binding sequence: The consensus binding sequence GACCACCCA for the three GLI transcription factors was first described by Kinzler et al. (Kinzler, et al., 1988) and many direct GLI target genes have been identified using the consensus binding sequence. Later, other natural non-consensus sequences have been found to be comparably active in the luciferase reporter assays in response to activated GLI2 expression (Winklmayr et al., 2010).
Structure: GLI2 belongs to the C2H2 type zinc finger domain protein family. It has a DNA binding domain of five zinc fingers, which are very highly homologous in the three GLIs. The crystal structure revealed by Pavlevich et al. (1993) showed that the fourth and fifth zinc fingers of GLI are responsible for all but one of the protein-DNA base contacts in a conserved nine base-pair region (Pavletich et al., 1993).
GLI2 protein has the repressor domain at N-terminus (Roessler et al., 2005) and activation domain at its C-terminus (Figure1). Unmasking of the strong activation potential of GLI2 through modulation of the N-terminal repression domain is one of the key mechanisms of the Shh signaling (Sasaki et al., 1999).
There is also a processing determinant domain of GLI2 at the C-terminal end of the protein and this domain was found to be the determining factor for the differential processing of the protein by proteasomes (Pan et al., 2007). It is a 197 aa residue between the zinc-finger DNA binding domain and first of 6 Protein Kinase A (PKA) site of GLI2 protein (Li et al., 2011).
In addition to proteolytic processing, alternative splicing may be another important regulatory mechanism for the modulation of repression and activation properties of the GLI2 protein and the generation of protein isoforms with different activities (Speek et al., 2006).
There is also a predicted nuclear export signal and nuclear localization signal domains in the GLI2 protein as depicted in Figure 1.
Expression In the integrative genome analysis of GLI2 orthologs, it was found that human GLI2 mRNA was expressed in embryonic stem cells, NT2 cells, fetal lung, fetal heart, regenerating liver, gastric cancer, and other tumors. Mouse GLI2 mRNA was expressed in unfertilized egg, ES cells, and EG cells (Katoh et al., 2008).
Localisation In a study tracking the cellular localization of GLI2, it has been described that GLI2 shuttles in and out of cilium and with the activation of HH signaling, the protein localizes to the nucleus from its primary cytoplasmic localization. However, exogenous GLI2 localizes into the cytoplasm (Kim et al., 2009a).
Function Hedgehog signaling mediated functions
GLI2 is one of the components of Hedgehog signaling and one of the three zinc finger transcription factors involved in this signaling pathway. GLI2 is thought to be the primary transcription activator of HH signaling along with GLI1 and to lesser extent GLI3 (Li et al., 2011). Hedgehog signaling pathway is a well characterized pathway and the role of GLI transcription factors are modeled distinctly in the absence or presence of HH ligands. In the absence of HH ligand, GLI proteins are processed and repressor forms are translocated into the nucleus whereas in the presence of HH ligand with the activation of SMO, the active forms of GLI proteins are translocated to the nucleus where they bind and activate their target gene expression (Javelaud et al., 2012). Processing of GLI2 and GLI3 N-terminus represents a critical mechanism allowing regulation of target genes. GLI2 functions as a primary activator of HH signaling along with GLI1 while GLI3 exhibits weak activity and is considered to function as a repressor. Due to the lack of repressor domain, GLI1 acts also as an activator where it is a direct target of GLI2 and has been shown to complement some of GLI2 functions in vivo (Dahmane et al., 1997; Ikram et al., 2004; Bai and Joyner, 2001).
There are some other proteins that participate in the transduction of the HH signaling by interacting with GLI proteins. An example is a serine/threonine kinase ULK3 is able to phosphorylate GLI proteins and promote their transcriptional activity but in the absence of HH signaling, ULK3 interacts with the inhibitory protein SUFU promoting GLI2 to its repressor form (Maloverjan et al., 2010). Another such proteins are DYRK, dual-specificity tyrosine-regulated kinases, DYRK2 acts as a scaffold protein for E3 unbiquitin ligase complex and phosphorylates GLI2 for proteasome degradation (Maddika et al., 2009) while DYRK1B inhibits GLI2 activity and promotes GLI3 repressor processing (Lauth et al., 2010).
Hedgehog signaling independent functions
GLI2 protein has also been found to be affected by other signaling pathways in hedgehog independent way stressing the importance of this protein. There are increasing evidences that GLI2 expression and activation is regulated by other signaling cascades and molecules.
In a study by Dennler et al. (2007), GLI2 has been shown to be a direct transcriptional target of the TGF-β/SMAD pathway independent from HH receptor signaling, and requires a functional Smad pathway in human normal fibroblasts and keratinocytes and cancer cell lines.
It has also been shown that GLI2 can induce the secretion of IL6 in stromal cells as a model of tumor microenvironment via sonic hedgehog independent signaling cascade and mediate increased immunoglobulin secretion in B-cell malignancies (Elsawa et al., 2011).
In a study on pancreatic cancer cells oncogenic KRAS strongly stimulated GLI function where this effect was ligand independent and occurred downstream of SMO since Cyclopamine treatment did not inhibit the KRAS induced GLI superactivation (Ji et al., 2007).
TGF-β, β-catenin and hyperactive RAS/RAF/MEK/ERK-mediated signaling upregulates GLI2 expression/activity in tumor cells independent of the presence of hedgehog ligand and hyperactivity of these alternate cell signaling pathways is known to occur in many different types of cancer (Jenkins, 2009; Lauth and Toftgard, 2007).
GLI2 and the tumor microenvironment.
Metastasizing tumor cells hijack many of the pathways that play major roles during normal development. Many of the embryonic developmental signaling pathways, such as Wnt, Hedgehog (HH), and Notch pathways, affect the survival of tumor stem cells and orchestrate a complex microenvironment that promotes tumor survival and progression (Das et al., 2012). In this context, several studies have addressed a putative role of GLI2 in the tumor microenvironment in mediating the cellular crosstalk in certain cancers.
Evidence of the crosstalk between TGF-beta and HH signaling pathways exists in non-canonical HH signaling pathway which could challenge cancer therapy (Javelaud et al., 2012). TGF-beta signalling is known to modulate the tumor microenviroment by orchestrating fibroblast chemotaxis and activation of immune cells and stromal-epithelial cross-talk (Stover et al., 2007). TGF-β also induces GLI2 expression in various human cell types, including normal fibroblasts and keratinocytes, as well as various cancer cell lines affecting tumor progression, apoptosis and cell cycle (Javelaud et al., 2011a). To date, the precise role of TGF- β-GLI2 signaling axis in the tumor microenvironment has not been addressed.
One study stressing the role of GLI2 on tumor microenvironment showed that GLI2 can mediate secretion of IL-6 in bone marrow stromal cells via a SHH-independent signaling cascade. The cytokine CCL5 initiates signaling through the CCR3 receptor leading to activation of the PI3K/AKT signaling pathway ultimately increasing the expression of IL-6. IL-6 in turn leads to increased immunoglobulin secretion by malignant B-cells (Elsawa et al., 2011).
A role for GLI2 in the tumor microenvironment in breast cancer metastasizing to the bone has been described. The production of parathyroid hormone-related peptide (PTHrP), a major factor involved in tumor-induced osteolysis caused by metastatic breast cancers, is driven at least in part by GLI2 both in vitro and in vivo (Sterling et al., 2006).
In B-cell chronic lymphocytic leukemia (B-CLL), it has been demonstrated that inhibiting HH signaling in stroma inhibits bone marrow stromal cell-induced survival of B-CLL cells, suggesting a role for HH signaling in the survival of B-CLL cells evidence supported by gene expression profiling of primary B-CLL cells and disease progression of B-CLL patients with clinical outcome (Hegde et al., 2008).
Homology GLI2 shares 44 % sequence identity with GLI3 and is structurally more similar to GLI3.

Mutations

Note Loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like mid-facial hypoplasia (Roessler et al., 2003).

Implicated in

Note
  
Entity Various cancers
Note GLI2 has been found to be expressed and affect various types of cancer cells and has been a candidate for novel therapeutic applications in the treatment of various cancers.
  
  
Entity Epidermal cancer
Note In epidermal malignancies, human GLI2 has been shown to antagonize contact inhibition and epidermal differentiation. Induction of GLI2 oncogene in human keratinocytes activates the transcription of a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L, while it represses genes associated with epidermal differentiation, suggesting a role for GLI2 in HH-induced epidermal neoplasia by opposing epithelial cell cycle arrest signals and epidermal differentiation (Regl et al., 2004). Basal GLI2 expression in melanoma cells largely depends upon autocrine TGF-β signaling and high levels of GLI2 expression is associated with loss of E-cadherin expression and increased invasive capacities (Alexaki et al., 2009; Javelaud et al., 2011b).
  
  
Entity Basal cell carcinoma
Note GLI2 plays a key role in activation of the activin/ Bone Morphogenic Protein (BMP) antagonist FST in response to HH signaling in basal cell carcinoma (BCC). This provides new evidence for a regulatory interaction between HH and activin/BMP signaling in hair follicle development and BCC (Eichberger et al., 2008). GLI2 has also been found to render cells resistant to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-mediated cell death in BCC by directly regulating cFlip and Bcl-2 (Kump et al., 2008). Together, these data suggest a novel therapeutic approach of targeting GLI2 in tumors with dysregulated Hedgehog signaling. Apart from that, it has been demonstrated that GLI2 directly activates GLI1 by binding the GLI-binding consensus sequence in the GLI1 promoter and retrovirally expressed GLI2 induces the expression of endogenous GLI1 in human primary keratinocytes (Ikram et al., 2004). There is also a positive GLI1-GLI2 feedback loop in HH-mediated epidermal cell proliferation (Regl et al., 2002). GLI2 has been shown to be expressed in the interfollicular epidermis and the outer root sheath of hair follicles in normal skin as well as in BCC tumor islands implicating GLI2 in regulating epidermal cell proliferation and skin tumorigenesis (Ikram et al., 2004).
  
  
Entity Prostate cancer
Note The role of GLI2 in maintaining the tumorigenic properties and growth of prostate cancer cells has been demonstrated suggesting that GLI2 could be a therapeutic target for the treatment of prostate cancer (Thiyagarajan et al., 2007). GLI2 protein is overexpressed in prostate cancer cell lines and primary prostate tumors, whereas the level of GLI2 mRNA is not appreciably different in normal and neoplastic prostate and GLI2 expression has been shown to be regulated by beta-Transducin Repeat Containing Protein 2 (BTrCP2) in HH pathway-associated human prostate cancer (Bhatia et al., 2006).
  
  
Entity Colon cancer
Note Targeting of the smoothened receptor (SMO) using cyclopamine had a minimal effect on colon cancer cell survival in comparison to the inhibition of GLI (using GANT61), which induced extensive cell death in 7/7 human colon carcinoma cell lines suggesting that GLI transcription factors may constitute a molecular switch that determines the balance between cell survival and cell death in human colon carcinoma (Mazumdar et al., 2011a). GANT61 specifically targeted GLI1 and GLI2 substantiated by specific inhibition of (i) direct binding of GLI1 and GLI2 to the promoters of target genes Huntingtin Interacting Protein 1 (HIP1) and BCL-2, (ii) GLI-luciferase activity, and (iii) transcriptional activation of BCL-2. These findings establish that inhibition of HH signaling at the level of the GLI genes is critical in the induction of DNA damage in early S-phase, leading to cell death in human colon carcinoma cells (Mazumdar et al., 2011b).
  
  
Entity Pancreatic cancer
Note In pancreatic cancers, recent evidence from in vitro and in vivo studies suggests that the Sonic Hedgehog (SHH) signaling pathway is aberrantly reactivated and recognized as one of the mediators in the majority of pancreatic cancers (PCs) (Ogden et al., 2004). Therefore, SHH blockade has the potential to prevent disease progression and pancreatic cancer metastases (Yauch et al., 2008). Sustained GLI2 activity has been shown to inhibit cell viability and induce apoptosis in pancreatic cancer cell lines and pancreatic cancer stem cells (CSCs) while activated GLI genes repress death receptors (DRs) and Fas expression, up-regulate the expressions of Bcl-2 and Platelet-derived Growth Factor Receptor alpha precursor (PDGFRα) and facilitate cell survival (Singh et al., 2011). In studies in which an activated version of the GLI2 transcription factor was expressed in β-cells that are also devoid of primary cilia, there was impaired β-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice (Landsman et al., 2011). This phenotype was accompanied by reduced expression of both genes critical for β-cell function and transcription factors associated with their mature phenotype indicating that deregulation of the HH pathway impairs β-cell function by interfering with the mature β-cell differentiation state (Landsman et al., 2011).
  
  
Entity Breast cancer
Note In frequent metastatic breast cancer to the bone where tumor cells receive signals such as Transforming Growth Factor- beta (TGF-β), this results in an upregulation of GLI2 expression and, in turn, increases the secretion of important osteolytic factors such as parathyroid hormone-related protein (PTHrP) (Johnson et al., 2011b). The guanosine nucleotide 6-thioguanine (6-TG) inhibits PTHrP expression and blocks osteolytic bone destruction in mice inoculated with bone metastatic cells though GLI2 signaling. This suggests that the clinical use of 6-TG or other guanosine nucleotides may be a viable therapeutic option in tumor types expressing elevated levels of GLI proteins (Johnson et al., 2011a).
  
  
Entity Liver cancer
Note Aberrant expression of Hedgehog components have been reported in hepatocellular carcinoma (HCC) (Kim et al., 2007). A role for GLI2 has been addressed to predominantly affect HCC susceptibility to TRAIL and cell proliferation (Zhang et al., 2011). Among the expression levels of Hedgehog pathway components, GLI2 levels were higher in human HCC lines compared with normal liver as well as in tumor tissue from HCC patients (Kim et al., 2006).
  
  
Entity B-cell cancers
Note In B-cell malignancies such as Waldenström macroglobulinemia (WM) and others including multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS), it has been shown that GLI2 can induce the secretion of the proinflammatory cytokine IL-6 in the surrounding stromal cells via PI3K/AKT signaling cascade and mediates increased immunoglobulin secretion by malignant B-cells (Elsawa et al., 2011).
In multiple myeloma, the mitogen-activated protein kinase MEK1 modulates GLI2 both at the mRNA and protein level. Constitutively activated MEK1 prolonged the half-life of GLI2 and increased its nuclear translocation, accompanied by attenuated ubiquitination of GLI2 protein in several MM cells relative to normal B cells (Liu et al., 2009). Moreover, combined treatment with RSK, a protein kinase functioning downstream of MEK-ERK cascade and GLI inhibitors led to an enhanced apoptosis of MM cells indicating that MEK-RSK cascade positively regulates GLI2 stabilization and represses its degradation via inhibiting Glycogen Synthase Kinase 3 beta (GSK-3β)-dependent phosphorylation and ubiquitination of GLI2 (Liu et al., 2012).
In diffuse large B-cell lymphoma (DLBCL), cancerous cells have been found to express GLI2 along with other sonic hedgehog proteins, providing evidence that dysregulation of the SHH pathway may be involved in the pathogenesis of the disease (Kim et al., 2009b).
In Mantle cell lymphoma (MCL), GLI2 was expressed along with SHH-GLI signaling proteins and perturbation of this signaling in the presence of exogenous SHH/cyclopamine significantly influenced the proliferation of malignant cells (Hegde et al., 2008). Furthermore, down-regulation of GLI transcription not only resulted in significantly decreased proliferation of the MCL cells but also significantly increased their susceptibility to doxorubicin, a standard chemotherapeutic drug used for MCL treatment (Hegde et al., 2008). Down-regulation of GLI 1 and GLI2 decreased cyclin D1 and BCL2 transcripts, suggesting these key molecules might be regulated by GLI proteins in MCL therefore molecular targeting of GLI is a potential therapeutic approach to improve the treatment for MCL patients (Hegde et al., 2008).
  
  
Entity Ovarian cancer
Note In ovarian cancer, targeting Jagged1, the ligand of Notch in tumor cells downregulates GLI2, thereby partly induces apoptosis, reduces cell viability, and reverses taxane-mediated effects in vitro and in vivo (Steg et al., 2011).
  
  
Entity Osteosarcoma
Note GLI2 was found to be overexpressed in human osteosarcoma biopsy specimens and knockdown by RNA interferences prevented osteosarcoma growth and anchorage-independent growth (Nagao et al., 2011). Also, knockdown of GLI2 promoted the arrest of osteosarcoma cells in G(1) phase and was accompanied by reduced protein expression of the cell cycle accelerators cyclin D1, S-phase associated kinase (SKP2) and phosphorylated Retinoblastoma protein (Rb) but increased the expression of p21(cip1). In addition, over-expression of GLI2 promoted mesenchymal stem cell proliferation and accelerated their cell cycle progression. Finally, evaluation of mouse xenograft models showed that GLI2 knockdown inhibited the growth of osteosarcoma in nude mice suggesting inhibition of GLI2 as an effective therapeutic approach for patients with osteosarcoma (Nagao et al., 2011).
  
  
Entity GLI2 in stem cells
Note In multipotential neural stem cells (NSCs) in the central nervous system (CNS), expression of the sox2 gene, which is essential for the maintenance of NSCs, is regulated by GLI2 (Takanaga et al., 2009). GLI2 binds to an enhancer that is vital for sox2 expression in telencephalic neuroepithelial (NE) cells, which consist of NSCs and neural precursor cells. Downregulation of GLI2 in NE cells in vitro and in vivo inhibits cell proliferation and the expression of Sox2 and other NSC markers, including Hes1, Hes5, Notch1, CD133, and Bmi1 (Takanaga et al., 2009). This also induces premature neuronal differentiation in the developing NE cells. In addition, Sox2 expression decreases significantly in the developing neuroepithelium of GLI2-deficient mice revealing a novel transcriptional cascade, involving GLI2→Sox2→Hes5, which maintains the undifferentiated state of telencephalic NE cells (Takanaga et al., 2009).
In embryonic stem cells, important molecules in the development of embryonic heart muscle and enhancers of cardiomyogenesis, GLI2 and myocyte enhancer factor 2C (MEF2C) are able to bind each other's regulatory elements, activate each other's expression and form a protein complex that synergistically activates transcription, enhancing cardiac muscle development (Voronova et al., 2012).
GLI2 overexpression and p53 deficiency has been shown to promote the progression of benign cartilage tumors to malignant state in a mouse model (Ho et al., 2009).
  

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PMID 20643644
 
Assignment of the human GLI2 gene to 2q14 by fluorescence in situ hybridization.
Matsumoto N, Fujimoto M, Kato R, Niikawa N.
Genomics. 1996 Aug 15;36(1):220-1.
PMID 8812445
 
Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells.
Mazumdar T, Devecchio J, Agyeman A, Shi T, Houghton JA.
Cancer Res. 2011b Sep 1;71(17):5904-14. doi: 10.1158/0008-5472.CAN-10-4173. Epub 2011 Jul 11.
PMID 21747117
 
Role of GLI2 in the growth of human osteosarcoma.
Nagao H, Ijiri K, Hirotsu M, Ishidou Y, Yamamoto T, Nagano S, Takizawa T, Nakashima K, Komiya S, Setoguchi T.
J Pathol. 2011 Jun;224(2):169-79. doi: 10.1002/path.2880. Epub 2011 Apr 19.
PMID 21506130
 
Regulation of Hedgehog signaling: a complex story.
Ogden SK, Ascano M Jr, Stegman MA, Robbins DJ.
Biochem Pharmacol. 2004 Mar 1;67(5):805-14. (REVIEW)
PMID 15104233
 
A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome.
Pan Y, Wang B.
J Biol Chem. 2007 Apr 13;282(15):10846-52. Epub 2007 Feb 5.
PMID 17283082
 
Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers.
Pavletich NP, Pabo CO.
Science. 1993 Sep 24;261(5129):1701-7.
PMID 8378770
 
The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells.
Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Ikram MS, Quinn AG, Philpott MP, Frischauf AM, Aberger F.
Oncogene. 2004 Feb 12;23(6):1263-74.
PMID 14691458
 
Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma.
Regl G, Neill GW, Eichberger T, Kasper M, Ikram MS, Koller J, Hintner H, Quinn AG, Frischauf AM, Aberger F.
Oncogene. 2002 Aug 15;21(36):5529-39.
PMID 12165851
 
A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2.
Roessler E, Ermilov AN, Grange DK, Wang A, Grachtchouk M, Dlugosz AA, Muenke M.
Hum Mol Genet. 2005 Aug 1;14(15):2181-8. Epub 2005 Jun 30.
PMID 15994174
 
The GLI-Kruppel family of human genes.
Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML, Seuanez HN, O'Brien SJ, Vogelstein B.
Mol Cell Biol. 1988 Aug;8(8):3104-13.
PMID 2850480
 
Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling.
Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H.
Development. 1999 Sep;126(17):3915-24.
PMID 10433919
 
Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms.
Singh BN, Fu J, Srivastava RK, Shankar S.
PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
PMID 22087285
 
A potential role of alternative splicing in the regulation of the transcriptional activity of human GLI2 in gonadal tissues.
Speek M, Njunkova O, Pata I, Valdre E, Kogerman P.
BMC Mol Biol. 2006 Mar 23;7:13.
PMID 16553965
 
Targeting the notch ligand JAGGED1 in both tumor cells and stroma in ovarian cancer.
Steg AD, Katre AA, Goodman B, Han HD, Nick AM, Stone RL, Coleman RL, Alvarez RD, Lopez-Berestein G, Sood AK, Landen CN.
Clin Cancer Res. 2011 Sep 1;17(17):5674-85. doi: 10.1158/1078-0432.CCR-11-0432. Epub 2011 Jul 13.
PMID 21753153
 
The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells.
Sterling JA, Oyajobi BO, Grubbs B, Padalecki SS, Munoz SA, Gupta A, Story B, Zhao M, Mundy GR.
Cancer Res. 2006 Aug 1;66(15):7548-53.
PMID 16885353
 
A delicate balance: TGF-beta and the tumor microenvironment.
Stover DG, Bierie B, Moses HL.
J Cell Biochem. 2007 Jul 1;101(4):851-61. (REVIEW)
PMID 17486574
 
Gli2 is a novel regulator of sox2 expression in telencephalic neuroepithelial cells.
Takanaga H, Tsuchida-Straeten N, Nishide K, Watanabe A, Aburatani H, Kondo T.
Stem Cells. 2009 Jan;27(1):165-74. doi: 10.1634/stemcells.2008-0580.
PMID 18927476
 
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.
Tanimura A, Dan S, Yoshida M.
J Virol. 1998 May;72(5):3958-64.
PMID 9557682
 
Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells.
Thiyagarajan S, Bhatia N, Reagan-Shaw S, Cozma D, Thomas-Tikhonenko A, Ahmad N, Spiegelman VS.
Cancer Res. 2007 Nov 15;67(22):10642-6.
PMID 18006803
 
Gli2 and MEF2C activate each other's expression and function synergistically during cardiomyogenesis in vitro.
Voronova A, Al Madhoun A, Fischer A, Shelton M, Karamboulas C, Skerjanc IS.
Nucleic Acids Res. 2012 Apr;40(8):3329-47. doi: 10.1093/nar/gkr1232. Epub 2011 Dec 22.
PMID 22199256
 
Non-consensus GLI binding sites in Hedgehog target gene regulation.
Winklmayr M, Schmid C, Laner-Plamberger S, Kaser A, Aberger F, Eichberger T, Frischauf AM.
BMC Mol Biol. 2010 Jan 13;11:2. doi: 10.1186/1471-2199-11-2.
PMID 20070907
 
A paracrine requirement for hedgehog signalling in cancer.
Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ.
Nature. 2008 Sep 18;455(7211):406-10. doi: 10.1038/nature07275. Epub 2008 Aug 27.
PMID 18754008
 
shRNA-mediated silencing of Gli2 gene inhibits proliferation and sensitizes human hepatocellular carcinoma cells towards TRAIL-induced apoptosis.
Zhang D, Liu J, Wang Y, Chen J, Chen T.
J Cell Biochem. 2011 Nov;112(11):3140-50. doi: 10.1002/jcb.23240.
PMID 21695716
 

Citation

This paper should be referenced as such :
Amarsaikhan, N ; Elsawa, SF
GLI2 (GLI family zinc finger 2)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):516-522.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GLI2ID40718ch2q14.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Soft Tissues: Pericytoma with t(7;12)(p22;q13) ACTB/GLI1
Nervous system: Astrocytoma with t(1;17)(p36;q21) SPOP/PRDM16


External links

Nomenclature
HGNC (Hugo)GLI2   4318
Cards
AtlasGLI2ID40718ch2q14
Entrez_Gene (NCBI)GLI2  2736  GLI family zinc finger 2
AliasesCJS; HPE9; PHS2; THP1; 
THP2
GeneCards (Weizmann)GLI2
Ensembl hg19 (Hinxton)ENSG00000074047 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000074047 [Gene_View]  chr2:120797291-120992653 [Contig_View]  GLI2 [Vega]
ICGC DataPortalENSG00000074047
TCGA cBioPortalGLI2
AceView (NCBI)GLI2
Genatlas (Paris)GLI2
WikiGenes2736
SOURCE (Princeton)GLI2
Genetics Home Reference (NIH)GLI2
Genomic and cartography
GoldenPath hg38 (UCSC)GLI2  -     chr2:120797291-120992653 +  2q14.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GLI2  -     2q14.2   [Description]    (hg19-Feb_2009)
EnsemblGLI2 - 2q14.2 [CytoView hg19]  GLI2 - 2q14.2 [CytoView hg38]
Mapping of homologs : NCBIGLI2 [Mapview hg19]  GLI2 [Mapview hg38]
OMIM165230   610829   615849   
Gene and transcription
Genbank (Entrez)AB007295 AB007296 AB007297 AB007298 AB209354
RefSeq transcript (Entrez)NM_005270 NM_030379 NM_030380 NM_030381
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)GLI2
Cluster EST : UnigeneHs.111867 [ NCBI ]
CGAP (NCI)Hs.111867
Alternative Splicing GalleryENSG00000074047
Gene ExpressionGLI2 [ NCBI-GEO ]   GLI2 [ EBI - ARRAY_EXPRESS ]   GLI2 [ SEEK ]   GLI2 [ MEM ]
Gene Expression Viewer (FireBrowse)GLI2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2736
GTEX Portal (Tissue expression)GLI2
Protein : pattern, domain, 3D structure
UniProt/SwissProtP10070   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP10070  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP10070
Splice isoforms : SwissVarP10070
PhosPhoSitePlusP10070
Domaine pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
Conserved Domain (NCBI)GLI2
DMDM Disease mutations2736
Blocks (Seattle)GLI2
SuperfamilyP10070
Human Protein AtlasENSG00000074047
Peptide AtlasP10070
HPRD01312
IPIIPI00018888   IPI00784005   IPI00221102   IPI00332823   IPI00914989   IPI00872649   IPI00941866   IPI00927450   IPI00436311   IPI00927580   
Protein Interaction databases
DIP (DOE-UCLA)P10070
IntAct (EBI)P10070
FunCoupENSG00000074047
BioGRIDGLI2
STRING (EMBL)GLI2
ZODIACGLI2
Ontologies - Pathways
QuickGOP10070
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  skeletal system development  in utero embryonic development  kidney development  chondrocyte differentiation  osteoblast development  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  nucleolus  cytosol  axoneme  transcription from RNA polymerase II promoter  smoothened signaling pathway  pattern specification process  axon guidance  ventral midline development  hindgut morphogenesis  heart development  transcription factor binding  zinc ion binding  cell proliferation  regulation of smoothened signaling pathway  response to mechanical stimulus  anterior/posterior pattern specification  proximal/distal pattern formation  membrane  nuclear speck  floor plate formation  spinal cord dorsal/ventral patterning  ventral spinal cord development  cerebellar cortex morphogenesis  smoothened signaling pathway involved in ventral spinal cord interneuron specification  smoothened signaling pathway involved in spinal cord motor neuron cell fate specification  smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation  spinal cord ventral commissure morphogenesis  pituitary gland development  lung development  mammary gland development  hindbrain development  motile cilium  negative regulation of chondrocyte differentiation  positive regulation of T cell differentiation in thymus  tube development  odontogenesis of dentin-containing tooth  embryonic digit morphogenesis  negative regulation of apoptotic process  sequence-specific DNA binding  positive regulation of neuron differentiation  positive regulation of DNA replication  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  embryonic digestive tract development  developmental growth  neuron development  branching morphogenesis of an epithelial tube  notochord regression  prostatic bud formation  mammary gland duct morphogenesis  smoothened signaling pathway involved in dorsal/ventral neural tube patterning  cellular response to organic cyclic compound  cochlea morphogenesis  ciliary tip  ciliary base  promoter-specific chromatin binding  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  skeletal system development  in utero embryonic development  kidney development  chondrocyte differentiation  osteoblast development  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  nucleolus  cytosol  axoneme  transcription from RNA polymerase II promoter  smoothened signaling pathway  pattern specification process  axon guidance  ventral midline development  hindgut morphogenesis  heart development  transcription factor binding  zinc ion binding  cell proliferation  regulation of smoothened signaling pathway  response to mechanical stimulus  anterior/posterior pattern specification  proximal/distal pattern formation  membrane  nuclear speck  floor plate formation  spinal cord dorsal/ventral patterning  ventral spinal cord development  cerebellar cortex morphogenesis  smoothened signaling pathway involved in ventral spinal cord interneuron specification  smoothened signaling pathway involved in spinal cord motor neuron cell fate specification  smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation  spinal cord ventral commissure morphogenesis  pituitary gland development  lung development  mammary gland development  hindbrain development  motile cilium  negative regulation of chondrocyte differentiation  positive regulation of T cell differentiation in thymus  tube development  odontogenesis of dentin-containing tooth  embryonic digit morphogenesis  negative regulation of apoptotic process  sequence-specific DNA binding  positive regulation of neuron differentiation  positive regulation of DNA replication  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  embryonic digestive tract development  developmental growth  neuron development  branching morphogenesis of an epithelial tube  notochord regression  prostatic bud formation  mammary gland duct morphogenesis  smoothened signaling pathway involved in dorsal/ventral neural tube patterning  cellular response to organic cyclic compound  cochlea morphogenesis  ciliary tip  ciliary base  promoter-specific chromatin binding  
Pathways : BIOCARTASonic Hedgehog (Shh) Pathway [Genes]   
Pathways : KEGGHedgehog signaling pathway    Hippo signaling pathway    Pathways in cancer    Basal cell carcinoma   
NDEx NetworkGLI2
Atlas of Cancer Signalling NetworkGLI2
Wikipedia pathwaysGLI2
Orthology - Evolution
OrthoDB2736
GeneTree (enSembl)ENSG00000074047
Phylogenetic Trees/Animal Genes : TreeFamGLI2
HOVERGENP10070
HOGENOMP10070
Homologs : HomoloGeneGLI2
Homology/Alignments : Family Browser (UCSC)GLI2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGLI2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GLI2
dbVarGLI2
ClinVarGLI2
1000_GenomesGLI2 
Exome Variant ServerGLI2
ExAC (Exome Aggregation Consortium)GLI2 (select the gene name)
Genetic variants : HAPMAP2736
Genomic Variants (DGV)GLI2 [DGVbeta]
DECIPHERGLI2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGLI2 
Mutations
ICGC Data PortalGLI2 
TCGA Data PortalGLI2 
Broad Tumor PortalGLI2
OASIS PortalGLI2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGLI2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGLI2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GLI2
DgiDB (Drug Gene Interaction Database)GLI2
DoCM (Curated mutations)GLI2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GLI2 (select a term)
intoGenGLI2
NCG5 (London)GLI2
Cancer3DGLI2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM165230    610829    615849   
Orphanet20436    20435    18904    23116    12618    12486    12484    12485   
MedgenGLI2
Genetic Testing Registry GLI2
NextProtP10070 [Medical]
TSGene2736
GENETestsGLI2
Target ValidationGLI2
Huge Navigator GLI2 [HugePedia]
snp3D : Map Gene to Disease2736
BioCentury BCIQGLI2
ClinGenGLI2 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2736
Chemical/Pharm GKB GenePA28721
Clinical trialGLI2
Miscellaneous
canSAR (ICR)GLI2 (select the gene name)
Probes
Litterature
PubMed123 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGLI2
EVEXGLI2
GoPubMedGLI2
iHOPGLI2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:03:40 CEST 2017

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