Skip to main content

Glioma-Associated Oncogene 1 (GLI1)

  • Reference work entry
  • First Online:
  • 147 Accesses

Synonyms

GLI; GLI family zinc finger 1; Glioma-associated oncogene family member 1

Historical Background and GLI Family Tree

Vogelstein and colleagues discovered GLI1 (Kinzler et al. 1987) as an amplified gene in a human glioma cell line derived from a 46-year-old male patient. The investigation utilized a denaturation-renaturation gel technique to identify DNA regions that are extensively amplified which led to the observation of a greater than 50-fold amplification of a novel gene, originally named GLI (Kinzler et al. 1987). Cloning and sequencing of the GLI gene showed that its predicted protein product contained five C2H2 zinc fingers and was structurally related to the Kruppel gene family (Kinzler et al. 1988; Ruppert et al. 1988). After the cloning of additional GLI-related genes, GLI was renamed GLI1 (Ruppert et al. 1988; Ruiz i Altaba 1999).

In vertebrates, the GLI gene family consists of GLI1, GLI2, and GLI3. The encoded GLI proteins have regions of high homology, but each...

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   4,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   4,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Aberger F, Ruiz IAA. Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy. Semin Cell Dev Biol. 2014;33:93–104.

    Article  PubMed  PubMed Central  Google Scholar 

  • Agarwal NK, Kim CH, Kunkalla K, Konno H, Tjendra Y, Kwon D, et al. Active IKKbeta promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma. Blood. 2016;127(5):605–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Agyeman A, Jha BK, Mazumdar T, Houghton JA. Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding. Oncotarget. 2014;5(12):4492–503.

    Article  PubMed  PubMed Central  Google Scholar 

  • Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med. 2013;19(11):1410–22.

    Article  PubMed  CAS  Google Scholar 

  • Atwood SX, Li M, Lee A, Tang JY, Oro AE. GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature. 2013;494(7438):484–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Aza-Blanc P, Lin HY, Ruiz i Altaba A, Kornberg TB. Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities. Development. 2000;127(19):4293–301.

    PubMed  Google Scholar 

  • Bai CB, Auerbach W, Lee JS, Stephen D, Joyner AL. GLI2, but not GLI1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development. 2002;129(20):4753–61.

    PubMed  CAS  Google Scholar 

  • Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148–60.

    Article  PubMed  CAS  Google Scholar 

  • Bolanos AL, Milla CM, Lira JC, Ramirez R, Checa M, Barrera L, et al. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am J Phys Lung Cell Mol Phys. 2012;303(11):L978–90.

    CAS  Google Scholar 

  • Bosco-Clement G, Zhang F, Chen Z, Zhou HM, Li H, Mikami I, et al. Targeting Gli transcription activation by small molecule suppresses tumor growth. Oncogene. 2014;33(16):2087–97.

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Bieber MM, Teng NN. Hedgehog signaling regulates drug sensitivity by targeting ABC transporters ABCB1 and ABCG2 in epithelial ovarian cancer. Mol Carcinog. 2014;53(8):625–34.

    PubMed  CAS  Google Scholar 

  • Choi SS, Omenetti A, Syn WK, Diehl AM. The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol. 2011;43(2):238–44.

    Article  PubMed  CAS  Google Scholar 

  • Cohen MM Jr. Hedgehog signaling update. Am J Med Genet A. 2010;152A(8):1875–914.

    Article  PubMed  CAS  Google Scholar 

  • Comba A, Almada LL, Tolosa EJ, Iguchi E, Marks DL, Vara Messler M, et al. Nuclear factor of activated T cells-dependent down-regulation of the transcription factor glioma-associated protein 1 (GLI1) underlies the growth inhibitory properties of arachidonic acid. J Biol Chem. 2016;291(4):1933–47.

    Article  PubMed  CAS  Google Scholar 

  • Cox B, Briscoe J, Ulloa F. SUMOylation by Pias1 regulates the activity of the Hedgehog dependent Gli transcription factors. PLoS One. 2010;5(8):e11996.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Denham M, Thompson LH, Leung J, Pebay A, Bjorklund A, Dottori M. GLI1 is an inducing factor in generating floor plate progenitor cells from human embryonic stem cells. Stem Cells. 2010;28(10):1805–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of GLI2 and GLI1 expression in vitro and in vivo. Cancer Res. 2007;67(14):6981–6.

    Article  PubMed  CAS  Google Scholar 

  • Di Magno L, Coni S, Di Marcotullio L, Canettieri G. Digging a hole under Hedgehog: downstream inhibition as an emerging anticancer strategy. Biochim Biophys Acta. 2015;1856(1):62–72.

    PubMed  Google Scholar 

  • Di Marcotullio L, Greco A, Mazza D, Canettieri G, Pietrosanti L, Infante P, et al. Numb activates the E3 ligase Itch to control GLI1 function through a novel degradation signal. Oncogene. 2011;30(1):65–76.

    Article  PubMed  CAS  Google Scholar 

  • El-Zaatari M, Kao JY, Tessier A, Bai L, Hayes MM, Fontaine C, et al. GLI1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets. PLoS One. 2013;8(3):e58935.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fernandez-Zapico ME. Primers on molecular pathways GLI: more than just Hedgehog? Pancreatology. 2008;8(3):227–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fiaschi M, Kolterud A, Nilsson M, Toftgard R, Rozell B. Targeted expression of GLI1 in the salivary glands results in an altered differentiation program and hyperplasia. Am J Pathol. 2011;179(5):2569–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E, et al. Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell. 2006;124(1):47–59.

    Article  PubMed  CAS  Google Scholar 

  • Harris LG, Samant RS, Shevde LA. Hedgehog signaling: networking to nurture a promalignant tumor microenvironment. Mol Cancer Res. 2011;9(9):1165–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heride C, Rigden DJ, Bertsoulaki E, Cucchi D, De Smaele E, Clague MJ, et al. The centrosomal deubiquitylase USP21 regulates GLI1 transcriptional activity and stability. J Cell Sci. 2016;129(21):4001–13.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513–37.

    Article  PubMed  CAS  Google Scholar 

  • Hwang RF, Moore TT, Hattersley MM, Scarpitti M, Yang B, Devereaux E, et al. Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer. Mol Cancer Res. 2012;10(9):1147–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Infante P, Mori M, Alfonsi R, Ghirga F, Aiello F, Toscano S, et al. GLI1/DNA interaction is a druggable target for Hedgehog-dependent tumors. EMBO J. 2015;34(2):200–17.

    Article  PubMed  CAS  Google Scholar 

  • Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med. 2010;16(12):1429–33.

    Article  PubMed  CAS  Google Scholar 

  • Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem. 2007;282(19):14048–55.

    Article  PubMed  CAS  Google Scholar 

  • Katoh Y, Katoh M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 2009;9(7):873–86.

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi I, Takahashi-Kanemitsu A, Sakiyama N, Tang C, Tang PJ, Noda S, et al. Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways. Nat Commun. 2016;7:12887.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kinzler KW, Vogelstein B. The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol. 1990;10(2):634–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, et al. Identification of an amplified, highly expressed gene in a human glioma. Science. 1987;236(4797):70–3.

    Article  PubMed  CAS  Google Scholar 

  • Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B. The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature. 1988;332(6162):371–4.

    Article  PubMed  CAS  Google Scholar 

  • Kramann R. Hedgehog Gli signalling in kidney fibrosis. Nephrol Dial Transplant. 2016;31(12):1989–95.

    Article  PubMed  CAS  Google Scholar 

  • Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, et al. Perivascular GLI1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell. 2015a;16(1):51–66.

    Article  PubMed  CAS  Google Scholar 

  • Kramann R, Fleig SV, Schneider RK, Fabian SL, DiRocco DP, Maarouf O, et al. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. J Clin Invest. 2015b;125(8):2935–51.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lauth M, Toftgard R. Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle. 2007;6(20):2458–63.

    Article  PubMed  CAS  Google Scholar 

  • Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA. 2007;104(20):8455–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee RT, Zhao Z, Ingham PW. Hedgehog signalling. Development. 2016;143(3):367–72.

    Article  PubMed  CAS  Google Scholar 

  • Li YH, Luo J, Mosley YY, Hedrick VE, Paul LN, Chang J, et al. AMP-activated protein kinase directly phosphorylates and destabilizes Hedgehog pathway transcription factor GLI1 in medulloblastoma. Cell Rep. 2015;12(4):599–609.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lo HW, Zhu H, Cao X, Aldrich A, Ali-Osman F. A novel splice variant of GLI1 that promotes glioblastoma cell migration and invasion. Cancer Res. 2009;69(17):6790–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lo Re AE, Fernandez-Barrena MG, Almada LL, Mills L, Elsawa SF, Lund G, et al. A novel AKT1-GLI3-VMP1 pathway mediates KRAS-induced autophagy in cancer cells. J Biol Chem. 2012;287(30):25325–34

    Google Scholar 

  • Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R, Xie W, et al. Regulation of GLI1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem. 2002;277(38):35156–61.

    Article  PubMed  CAS  Google Scholar 

  • Mazza D, Infante P, Colicchia V, Greco A, Alfonsi R, Siler M, et al. PCAF ubiquitin ligase activity inhibits Hedgehog/GLI1 signaling in p53-dependent response to genotoxic stress. Cell Death Differ. 2013;20(12):1688–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Merchant JL, Saqui-Salces M. Inhibition of Hedgehog signaling in the gastrointestinal tract: targeting the cancer microenvironment. Cancer Treat Rev. 2014;40(1):12–21.

    Article  PubMed  CAS  Google Scholar 

  • Merchant A, Joseph G, Wang Q, Brennan S, Matsui W. GLI1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood. 2010;115(12):2391–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L, Almada LL, et al. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem. 2013;288(17):11786–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mills LD, Zhang L, Marler R, Svingen P, Fernandez-Barrena MG, Dave M, et al. Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. J Biol Chem. 2014;289(23):16516–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mosimann C, Hausmann G, Basler K. The role of Parafibromin/Hyrax as a nuclear Gli/Ci-interacting protein in Hedgehog target gene control. Mech Dev. 2009;126(5–6):394–405.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura I, Fernandez-Barrena MG, Ortiz-Ruiz MC, Almada LL, Hu C, Elsawa SF, et al. Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration. J Biol Chem. 2013;288(29):21389–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nye MD, Almada LL, Fernandez-Barrena MG, Marks DL, Elsawa SF, Vrabel A, et al. The transcription factor GLI1 interacts with SMAD proteins to modulate transforming growth factor beta-induced gene expression in a p300/CREB-binding protein-associated factor (PCAF)-dependent manner. J Biol Chem. 2014;289(22):15495–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Palle K, Mani C, Tripathi K, Athar M. Aberrant GLI1 activation in DNA damage response, carcinogenesis and chemoresistance. Cancers (Basel). 2015;7(4):2330–51.

    Article  CAS  Google Scholar 

  • Pandolfi S, Stecca B. Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy. Expert Rev Mol Med. 2015;17:e5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, et al. Mouse GLI1 mutants are viable but have defects in SHH signaling in combination with a GLI2 mutation. Development. 2000;127(8):1593–605.

    PubMed  CAS  Google Scholar 

  • Pavletich NP, Pabo CO. Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers. Science. 1993;261(5129):1701–7.

    Article  PubMed  CAS  Google Scholar 

  • Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the Sonic Hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel). 2016;8(2):22.

    Article  CAS  Google Scholar 

  • Ruiz i Altaba A. Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 1999;15(10):418–25.

    Article  PubMed  CAS  Google Scholar 

  • Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML, et al. The GLI-Kruppel family of human genes. Mol Cell Biol. 1988;8(8):3104–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H. Regulation of GLI2 and GLI3 activities by an amino-terminal repression domain: implication of GLI2 and GLI3 as primary mediators of Shh signaling. Development. 1999;126(17):3915–24.

    PubMed  CAS  Google Scholar 

  • Schumacher MA, Donnelly JM, Engevik AC, Xiao C, Yang L, Kenny S, et al. Gastric Sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori. Gastroenterology. 2012;142(5):1150–9. e6.

    Article  PubMed  CAS  Google Scholar 

  • Sheng T, Chi S, Zhang X, Xie J. Regulation of GLI1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem. 2006;281(1):9–12.

    Article  PubMed  CAS  Google Scholar 

  • Shi Q, Han Y, Jiang J. Suppressor of fused impedes Ci/Gli nuclear import by opposing Trn/Kapbeta2 in Hedgehog signaling. J Cell Sci. 2014;127(Pt 5):1092–103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shi X, Wang Q, Gu J, Xuan Z, Wu JI. SMARCA4/BRG1 coordinates genetic and epigenetic networks underlying Shh-type medulloblastoma development. Oncogene. 2016;35(44):5746–58.

    Article  PubMed  CAS  Google Scholar 

  • Shimokawa T, Tostar U, Lauth M, Palaniswamy R, Kasper M, Toftgard R, et al. Novel human glioma-associated oncogene 1 (GLI1) splice variants reveal distinct mechanisms in the terminal transduction of the hedgehog signal. J Biol Chem. 2008;283(21):14345–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stecca B, Ruiz IAA. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol. 2010;2(2):84–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stecca B, Ruiz i Altaba A. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J. 2009;28(6):663–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Szczepny A, Wagstaff KM, Dias M, Gajewska K, Wang C, Davies RG, et al. Overlapping binding sites for importin beta1 and suppressor of fused (SuFu) on glioma-associated oncogene homologue 1 (GLI1) regulate its nuclear localization. Biochem J. 2014;461(3):469–76.

    Article  PubMed  CAS  Google Scholar 

  • Xu Q, Liu X, Zheng X, Yao Y, Wang M, Liu Q. The transcriptional activity of GLI1 is negatively regulated by AMPK through Hedgehog partial agonism in hepatocellular carcinoma. Int J Mol Med. 2014;34(3):733–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yoon JW, Liu CZ, Yang JT, Swart R, Iannaccone P, Walterhouse D. GLI activates transcription through a herpes simplex viral protein 16-like activation domain. J Biol Chem. 1998;273(6):3496–501.

    Article  PubMed  CAS  Google Scholar 

  • Yoon JW, Lamm M, Iannaccone S, Higashiyama N, Leong KF, Iannaccone P, et al. p53 modulates the activity of the GLI1 oncogene through interactions with the shared coactivator TAF9. DNA Repair. 2015;34:9–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhan X, Shi X, Zhang Z, Chen Y, Wu JI. Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development. Proc Natl Acad Sci USA. 2011;108(31):12758–63.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang R, Wu J, Ferrandon S, Glowacki KJ, Houghton JA. Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both transcription and DNA licensing. Oncotarget. 2016;7(49):80190–207.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin E. Fernandez-Zapico .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Ala’Aldeen, A., Marks, D.L., Olson, R.L.O., Fernandez-Zapico, M.E. (2018). Glioma-Associated Oncogene 1 (GLI1). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101890

Download citation

Publish with us

Policies and ethics