Skip to main content
SpringerLink
Log in
Book cover

Encyclopedia of Signaling Molecules pp 1–11Cite as

GLI Family Zinc Finger 2

  • Living reference work entry
  • First Online:

  • 57 Accesses

Synonyms

GLI2; GLI-Kruppel family member 2; Glioma-associated oncogene family zinc finger 2; HPE9; Oncogene GLI2; Tax helper protein 1; THP1; THP2

Historical Background

GLI2 belongs to the GLI family of genes, encoding Kruppel-like zinc finger transcription factors. Evidence for GLI proteins and their function was first elucidated through the characterization of the Drosophila GLI homolog Cubitus interruptus (Ci), responsible for proper tissue patterning and segmentation (Goodrich et al. 1996). While highly conserved, vertebrates have three different forms of the transcription factor (GLI1, GLI2, and GLI3), each taking on redundant and unique roles in normal and pathologic biology. GLI1, the first of the GLI family characterized in humans, was identified in 1987 as a highly expressed gene in human glioma (Kinzler et al. 1987). Both GLI2 and GLI3 were discovered in 1988 through the use of cloned GLI1 cDNA as a probe targeting similar sequences (Ruppert et al. 1988). The expression of...

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

References

  • Agyeman A, Mazumdar T, Houghton JA. Regulation of DNA damage following termination of Hedgehog (HH) survival signaling at the level of the GLI genes in human colon cancer. Oncotarget. 2012;3(8):854–68. PubMed PMID: 23097684. Pubmed Central PMCID: 3478462. Epub 2012/10/26. Eng.

    Article  PubMed  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. PubMed PMID: 24962990. Pubmed Central PMCID: 4147340. Epub 2014/06/26. Eng.

    Article  PubMed  PubMed Central  Google Scholar 

  • Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, et al. GLI2-mediated melanoma invasion and metastasis. J Natl Cancer Inst. 2010;102(15):1148–59. PubMed PMID: 20660365. Pubmed Central PMCID: 2914763.

    Article  CAS  PubMed  PubMed Central  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. PubMed PMID: 23446420. Pubmed Central PMCID: 3761364. Epub 2013/03/01. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atwood SX, Sarin KY, Whitson RJ, Li JR, Kim G, Rezaee M, et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell. 2015;27(3):342–53. PubMed PMID: 25759020. Pubmed Central PMCID: 4357167. Epub 2015/03/12. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen F, Mo J, Zhang L. Long noncoding RNA BCAR4 promotes osteosarcoma progression through activating GLI2-dependent gene transcription. Tumour Biol. 2016;37(10):13403–12. PubMed PMID: 27460090. Epub 2016/07/28. Eng.

    Article  CAS  PubMed  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. PubMed PMID: 17638910.

    Article  CAS  PubMed  Google Scholar 

  • Dennler S, Andre J, Verrecchia F, Mauviel A. Cloning of the human GLI2 promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation. J Biol Chem. 2009;284(46):31523–31. PubMed PMID: 19797115. Pubmed Central PMCID: 2797221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dentice M, Ambrosio R, Salvatore D. Role of type 3 deiodinase in cancer. Expert Opin Ther Targets. 2009;13(11):1363–73. PubMed PMID: 19764892. Epub 2009/09/22. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Dentice M, Luongo C, Ambrosio R, Sibilio A, Casillo A, Iaccarino A, et al. beta-Catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. Gastroenterology. 2012;143(4):1037–47. PubMed PMID: 22771508. Epub 2012/07/10. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Desch P, Asslaber D, Kern D, Schnidar H, Mangelberger D, Alinger B, et al. Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells. Oncogene. 2010;29(35):4885–95. PubMed PMID: 20603613. Epub 2010/07/07. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Elsawa SF, Almada LL, Ziesmer SC, Novak AJ, Witzig TE, Ansell SM, et al. GLI2 transcription factor mediates cytokine cross-talk in the tumor microenvironment. J Biol Chem. 2011;286(24):21524–34. PubMed PMID: 21454528. Pubmed Central PMCID: 3122211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743–54. PubMed PMID: 18813320. Pubmed Central PMCID: 4457317. Epub 2008/09/25. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faiao-Flores F, Alves-Fernandes DK, Pennacchi PC, Sandri S, Vicente AL, Scapulatempo-Neto C, et al. Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene 2016 17:1–13. PubMed PMID: 27748762.

    Google Scholar 

  • Fan YH, Ding J, Nguyen S, Liu XJ, Xu G, Zhou HY, et al. Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells. Oncogene. 2016;35(1):116–24. PubMed PMID: 25772244. Epub 2015/03/17. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 1996;10(3):301–12. PubMed PMID: 8595881. Epub 1996/02/01. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Gorojankina T. Hedgehog signaling pathway: a novel model and molecular mechanisms of signal transduction. Cell Mol Life Sci. 2016;73(7):1317–32. PubMed PMID: 26762301. Epub 2016/01/15. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC, et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet. 2000;24(3):216–7. PubMed PMID: 10700170. Epub 2000/03/04. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Hegde GV, Peterson KJ, Emanuel K, Mittal AK, Joshi AD, Dickinson JD, et al. Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol Cancer Res. 2008;6(12):1928–36. PubMed PMID: 19074837. Epub 2008/12/17. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med. 2000;343(3):185–9. PubMed PMID: 10900278. Epub 2000/07/20. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Huang L, Walter V, Hayes DN, Onaitis M. Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer. Clin Cancer Res. 2014;20(6):1566–75. PubMed PMID: 24423612. Pubmed Central PMCID: 4136748. Epub 2014/01/16. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513–37. PubMed PMID: 21801010. Epub 2011/08/02. eng.

    Article  CAS  PubMed  Google Scholar 

  • Hui CC, Slusarski D, Platt KA, Holmgren R, Joyner AL. Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm- and mesoderm-derived tissues suggests multiple roles during postimplantation development. Dev Biol. 1994;162(2):402–13. PubMed PMID: 8150204. Epub 1994/04/01. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Infante P, Alfonsi R, Botta B, Mori M, Di Marcotullio L. Targeting GLI factors to inhibit the Hedgehog pathway. Trends Pharmacol Sci. 2015;36(8):547–58. PubMed PMID: 26072120. Epub 2015/06/15. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Jackson DA, Smith TD, Amarsaikhan N, Han W, Neil MS, Boi SK, et al. Modulation of the IL-6 receptor alpha underlies GLI2-mediated regulation of Ig secretion in Waldenstrom macroglobulinemia cells. J Immunol.2015;195(6):2908–16. PubMed PMID: 26238488. Pubmed Central PMCID: 4561187. Epub 2015/08/05. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacob J, Briscoe J. Gli proteins and the control of spinal-cord patterning. EMBO Rep. 2003;4(8):761–5. PubMed PMID: 12897799 Pubmed Central PMCID: 1326336. Epub 2003/08/05. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Javelaud D, Alexaki VI, Pierrat MJ, Hoek KS, Dennler S, Van Kempen L, et al. GLI2 and M-MITF transcription factors control exclusive gene expression programs and inversely regulate invasion in human melanoma cells. Pigment Cell Melanoma Res. 2011;24(5):932–43. PubMed PMID: 21801332.

    Article  CAS  PubMed  Google Scholar 

  • Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52–67. PubMed PMID: 20371345. Pubmed Central PMCID: 2862057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kester MH, Kuiper GG, Versteeg R, Visser TJ. Regulation of type III iodothyronine deiodinase expression in human cell lines. Endocrinology. 2006;147(12):5845–54. PubMed PMID: 16935842. Epub 2006/08/29. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Kim JE, Singh RR, Cho-Vega JH, Drakos E, Davuluri Y, Khokhar FA, et al. Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma. Mod Pathol. 2009a;22(10):1312–20. PubMed PMID: 19593328. Epub 2009/07/14. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Kim KH, Kim JM, Choi YL, Shin YK, Lee HC, Seong IO, et al. Expression of sonic hedgehog signaling molecules in normal, hyperplastic and carcinomatous endometrium. Pathol Int. 2009b;59(5):279–87. PubMed PMID: 19432668. Epub 2009/05/13. Eng.

    Article  PubMed  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. PubMed PMID: 3563490. Epub 1987/04/03. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Kumar K, Raza SS, Knab LM, Chow CR, Kwok B, Bentrem DJ, et al. GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. Sci Rep. 2015;5:9489. PubMed PMID: 25807524. Pubmed Central PMCID: 4452877. Epub 2015/03/26. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luongo C, Ambrosio R, Salzano S, Dlugosz AA, Missero C, Dentice M. The sonic hedgehog-induced type 3 deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing Gli2 inactivation. Endocrinology. 2014;155(6):2077–88. PubMed PMID: 24693967. Epub 2014/04/04. Eng.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mazumdar T, Sandhu R, Qadan M, DeVecchio J, Magloire V, Agyeman A, et al. Hedgehog signaling regulates telomerase reverse transcriptase in human cancer cells. PloS one. 2013;8(9):e75253. PubMed PMID: 24086482. Pubmed Central PMCID: 3783395. Epub 2013/10/03. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mccleary-Wheeler A. From normal development to disease: the biochemistry and regulation of GLI2. Medical Epigenetics Med Epigenet. 2014;2(1):1–19.

    Article  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. PubMed PMID: 23482563. Pubmed Central PMCID: 3636867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagao H, Ijiri K, Hirotsu M, Ishidou Y, Yamamoto T, Nagano S, et al. Role of GLI2 in the growth of human osteosarcoma. J Pathol. 2011;224(2):169–79. PubMed PMID: 21506130.

    Article  CAS  PubMed  Google Scholar 

  • Nagao-Kitamoto H, Nagata M, Nagano S, Kitamoto S, Ishidou Y, Yamamoto T, et al. GLI2 is a novel therapeutic target for metastasis of osteosarcoma. Int J Cancer. 2015b;136(6):1276–84. PubMed PMID: 25082385. Epub 2014/08/02. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Nagao-Kitamoto H, Setoguchi T, Kitamoto S, Nakamura S, Tsuru A, Nagata M, et al. Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion. Cancer Lett. 2015a;356(2 Pt B):855–61. PubMed PMID: 25449781. Epub 2014/12/03. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Narita S, So A, Ettinger S, Hayashi N, Muramaki M, Fazli L, et al. GLI2 knockdown using an antisense oligonucleotide induces apoptosis and chemosensitizes cells to paclitaxel in androgen-independent prostate cancer. Clin Cancer Res. 2008;14(18):5769–77. PubMed PMID: 18794086. Epub 2008/09/17. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Pak E, Segal RA. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev Cell. 2016;38(4):333–44. PubMed PMID: 27554855. Pubmed Central PMCID: 5017307. Epub 2016/08/25. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Pantazi E, Gemenetzidis E, Trigiante G, Warnes G, Shan L, Mao X, et al. GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis. Cell Death Dis. 2014;5:e1028. PubMed PMID: 24481442. Pubmed Central PMCID: 4040660. Epub 2014/02/01. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierrat MJ, Marsaud V, Mauviel A, Javelaud D. Expression of microphthalmia-associated transcription factor (MITF), which is critical for melanoma progression, is inhibited by both transcription factor GLI2 and transforming growth factor-beta. J Biol Chem. 2012;287(22):17996–8004. PubMed PMID: 22496449. Pubmed Central PMCID: 3365743.

    Article  CAS  PubMed  PubMed Central  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). PubMed PMID: 26891329. Pubmed Central PMCID: 4773745. Epub 2016/02/20. Eng.

    Google Scholar 

  • Riobo NA, Lu K, Ai X, Haines GM, Emerson Jr CP. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA. 2006;103(12):4505–10. PubMed PMID: 16537363. Pubmed Central PMCID: 1450201.

    Article  CAS  PubMed  PubMed Central  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. PubMed PMID: 2850480. Pubmed Central PMCID: 363537. Epub 1988/08/01. Eng.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandri S, Faiao-Flores F, Tiago M, Pennacchi PC, Massaro RR, Alves-Fernandes DK, et al. Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation. Pharmacol Res. 2016;111:523–33. PubMed PMID: 27436149.

    Article  CAS  PubMed  Google Scholar 

  • Singh RR, Kim JE, Davuluri Y, Drakos E, Cho-Vega JH, Amin HM, et al. Hedgehog signaling pathway is activated in diffuse large B-cell lymphoma and contributes to tumor cell survival and proliferation. Leukemia. 2010;24(5):1025–36. PubMed PMID: 20200556. Epub 2010/03/05. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Singovski G, Bernal C, Kuciak M, Siegl-Cachedenier I, Conod A, Ruiz IAA. In vivo epigenetic reprogramming of primary human colon cancer cells enhances metastases. J Mol Cell Biol. 2016;8(2):157–73. PubMed PMID: 26031752. Pubmed Central PMCID: 4816146. Epub 2015/06/03. Eng.

    Article  PubMed  Google Scholar 

  • Sun Z, Zhang T, Hong H, Liu Q, Zhang H. miR-202 suppresses proliferation and induces apoptosis of osteosarcoma cells by downregulating Gli2. Mol Cell Biochem. 2014;397(1–-2):277–83. PubMed PMID: 25156120. Epub 2014/08/27. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. PubMed PMID: 25190079. Pubmed Central PMCID: 4176007.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tojo M, Kiyosawa H, Iwatsuki K, Nakamura K, Kaneko F. Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma. Br J Dermatol. 2003;148(5):892–7. PubMed PMID: 12786818. Epub 2003/06/06. Eng.

    Article  CAS  PubMed  Google Scholar 

  • Wu M, Ingram L, Tolosa EJ, Vera RE, Li Q, Kim S, et al. Gli transcription factors mediate the oncogenic transformation of prostate basal cells induced by a Kras-androgen receptor axis. J Biol Chem. 2016:25749–90. PubMed PMID: 27760825. Epub 2016/10/21. Eng.

    Google Scholar 

  • Yang W, Liu X, Choy E, Mankin H, Hornicek FJ, Duan Z. Targeting hedgehog-GLI-2 pathway in osteosarcoma. J Orthop Res. 2013;31(3):502–9. PubMed PMID: 22968906.

    Article  PubMed  Google Scholar 

  • Zhou J, Zhu G, Huang J, Li L, Du Y, Gao Y, et al. Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target. Cancer Lett. 2016;370(2):313–23. PubMed PMID: 26577809.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Northern Illinois University, DeKalb, 60115, IL, USA

    David A. Jackson, Jason A. Misurelli & Sherine F. Elsawa

Authors
  1. David A. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason A. Misurelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sherine F. Elsawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sherine F. Elsawa .

Editor information

Editors and Affiliations

  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media LLC

About this entry

Cite this entry

Jackson, D.A., Misurelli, J.A., Elsawa, S.F. (2017). GLI Family Zinc Finger 2. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_101917-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_101917-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-6438-9

  • Online ISBN: 978-1-4614-6438-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation