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GLI transcription factors: Mediators of oncogenic Hedgehog signalling

      Abstract

      The current concept of tumourigenesis holds that cancer results from the progressive acquisition of mutations that endow affected cells with selective growth advantages by activating multiple processes including intrinsic mitogenic and pro-survival pathways. Constitutive activation of the Hedgehog (HH)/GLI signalling cascade has recently been implicated in the growth of a number of human malignancies ranging from semi-malignant tumours of the skin to highly aggressive cancers of the brain, lung, pancreas and prostate. This review focuses on the role of the GLI zinc finger transcription factors, which mediate Hedgehog signalling at the distal end of the pathway. We summarise recent data on the mechanisms by which latent GLI proteins are activated in response to stimulation of Hedgehog signalling. Based on the identification of a growing number of direct GLI target genes, we propose that HH-driven tumourigenesis relies on multiple cellular processes such as promotion of G1/S phase progression, enhancement of cell survival by providing anti-apoptotic cues, increase in metastatic potential of Hedgehog responsive cells, and activation of potential tumour stem cells. In view of the critical role of GLI genes in Hedgehog-associated cancers, strategies that aim at interfering with GLI function are likely to represent efficient approaches in future targeted cancer therapy.

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      References

        • Ingham P.W.
        • McMahon A.P.
        Hedgehog signaling in animal development: paradigms and principles.
        Genes Dev. 2001; 15: 3059-3087
        • Pasca di Magliano M.
        • Hebrok M.
        Hedgehog signalling in cancer formation and maintenance.
        Nat Rev Cancer. 2003; 3: 903-911
        • Sanchez P.
        • Clement V.
        • i Altaba A.R.
        Therapeutic targeting of the Hedgehog-GLI pathway in prostate cancer.
        Cancer Res. 2005; 65: 2990-2992
        • Lum L.
        • Beachy P.A.
        The Hedgehog response network: sensors, switches, and routers.
        Science. 2004; 304: 1755-1759
        • Hooper J.E.
        • Scott M.P.
        Developmental cell biology: communicating with hedgehogs.
        Nat Rev Mol Cell Biol. 2005; 6: 306-317
        • Ruiz i Altaba A.
        • Sanchez P.
        • Dahmane N.
        Gli and hedgehog in cancer: tumours, embryos and stem cells.
        Nat Rev Cancer. 2002; 2: 361-372
        • Pavletich N.P.
        • Pabo C.O.
        Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers.
        Science. 1993; 261: 1701-1707
        • Kinzler K.W.
        • Vogelstein B.
        The GLI gene encodes a nuclear protein which binds specific sequences in the human genome.
        Mol Cell Biol. 1990; 10: 634-642
        • Sasaki H.
        • Nishizaki Y.
        • Hui C.
        • et al.
        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: 3915-3924
        • Wang B.
        • Fallon J.F.
        • Beachy P.A.
        Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.
        Cell. 2000; 100: 423-434
        • Shin S.H.
        • Kogerman P.
        • Lindstrom E.
        • et al.
        GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization.
        Proc Natl Acad Sci USA. 1999; 96: 2880-2884
        • Altaba A.R.
        Gli proteins encode context-dependent positive and negative functions: implications for development and disease.
        Development. 1999; 126: 3205-3216
        • Bai C.B.
        • Stephen D.
        • Joyner A.L.
        All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3.
        Dev Cell. 2004; 6: 103-115
        • Buttitta L.
        • Mo R.
        • Hui C.C.
        • et al.
        Interplays of Gli2 and Gli3 and their requirement in mediating SHH-dependent sclerotome induction.
        Development. 2003; 130: 6233-6243
        • Motoyama J.
        • Milenkovic L.
        • Iwama M.
        • et al.
        Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification.
        Dev Biol. 2003; 259: 150-161
        • Dai P.
        • Akimaru H.
        • Tanaka Y.
        • et al.
        Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3.
        J Biol Chem. 1999; 274: 8143-8152
        • Ikram M.S.
        • Neill G.W.
        • Regl G.
        • et al.
        GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter.
        J Invest Dermatol. 2004; 122: 1503-1509
        • Aza-Blanc P.
        • Ramirez-Weber F.A.
        • Laget M.P.
        • et al.
        Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
        Cell. 1997; 89: 1043-1053
        • Chen C.H.
        • von Kessler D.P.
        • Park W.
        • et al.
        Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression.
        Cell. 1999; 98: 305-316
        • Jia J.
        • Amanai K.
        • Wang G.
        • et al.
        Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus.
        Nature. 2002; 416: 548-552
        • Price M.A.
        • Kalderon D.
        Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A.
        Development. 1999; 126: 4331-4339
        • Price M.A.
        • Kalderon D.
        Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1.
        Cell. 2002; 108: 823-835
        • Jiang J.
        • Struhl G.
        Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.
        Nature. 1998; 391: 493-496
        • Lum L.
        • Zhang C.
        • Oh S.
        • et al.
        Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2.
        Mol Cell. 2003; 12: 1261-1274
        • Kogerman P.
        • Grimm T.
        • Kogerman L.
        • et al.
        Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1.
        Nat Cell Biol. 1999; 1: 312-319
        • Taylor M.D.
        • Liu L.
        • Raffel C.
        • et al.
        Mutations in SUFU predispose to medulloblastoma.
        Nat Genet. 2002; 31: 306-310
        • Cheng S.Y.
        • Bishop J.M.
        Suppressor of fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex.
        Proc Natl Acad Sci USA. 2002; 99: 5442-5447
        • Mill P.
        • Mo R.
        • Fu H.
        • et al.
        Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development.
        Genes Dev. 2003; 17: 282-294
        • Ding Q.
        • Motoyama J.
        • Gasca S.
        • et al.
        Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice.
        Development. 1998; 125: 2533-2543
        • Mao J.
        • Maye P.
        • Kogerman P.
        • et al.
        Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1.
        J Biol Chem. 2002; 22: 22
        • Callahan C.A.
        • Ofstad T.
        • Horng L.
        • et al.
        MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription.
        Genes Dev. 2004; 18: 2724-2729
        • Akimaru H.
        • Chen Y.
        • Dai P.
        • et al.
        Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling.
        Nature. 1997; 386: 735-738
        • Chen Y.
        • Goodman R.H.
        • Smolik S.M.
        Cubitus interruptus requires Drosophila CREB-binding protein to activate wingless expression in the Drosophila embryo.
        Mol Cell Biol. 2000; 20: 1616-1625
        • Huangfu D.
        • Liu A.
        • Rakeman A.S.
        • et al.
        Hedgehog signalling in the mouse requires intraflagellar transport proteins.
        Nature. 2003; 426: 83-87
        • Huangfu D.
        • Anderson K.V.
        Cilia and Hedgehog responsiveness in the mouse.
        Proc Natl Acad Sci USA. 2005;
        • Liu A.
        • Wang B.
        • Niswander L.A.
        Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors.
        Development. 2005; 132: 3103-3111
        • Nguyen V.
        • Chokas A.L.
        • Stecca B.
        • et al.
        Cooperative requirement of the Gli proteins in neurogenesis.
        Development. 2005; 132: 3267-3279
        • Gorlin R.J.
        Nevoid basal cell carcinoma syndrome.
        Dermatol Clin. 1995; 13: 113-125
        • Hahn H.
        • Wojnowski L.
        • Miller G.
        • et al.
        The patched signaling pathway in tumourigenesis and development: lessons from animal models.
        J Mol Med. 1999; 77 ([in process citation]): 459-468
        • Bale A.E.
        • Yu K.P.
        The hedgehog pathway and basal cell carcinomas.
        Hum Mol Genet. 2001; 10: 757-762
        • Goodrich L.V.
        • Scott M.P.
        Hedgehog and patched in neural development and disease.
        Neuron. 1998; 21: 1243-1257
        • Hahn H.
        • Wicking C.
        • Zaphiropoulous P.G.
        • et al.
        Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.
        Cell. 1996; 85: 841-851
        • Gailani M.R.
        • Stahle-Backdahl M.
        • Leffell D.J.
        • et al.
        The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.
        Nat Genet. 1996; 14 ([see comments]): 78-81
        • Johnson R.L.
        • Rothman A.L.
        • Xie J.
        • et al.
        Human homolog of patched, a candidate gene for the basal cell nevus syndrome.
        Science. 1996; 272: 1668-1671
        • Xie J.
        • Murone M.
        • Luoh S.M.
        • et al.
        Activating smoothened mutations in sporadic basal-cell carcinoma.
        Nature. 1998; 391: 90-92
        • Oro A.E.
        • Higgins K.M.
        • Hu Z.
        • et al.
        Basal cell carcinomas in mice overexpressing Sonic hedgehog.
        Science. 1997; 276: 817-821
        • Fan H.
        • Oro A.E.
        • Scott M.P.
        • et al.
        Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog.
        Nat Med. 1997; 3: 788-792
        • Aszterbaum M.
        • Epstein J.
        • Oro A.
        • et al.
        Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.
        Nat Med. 1999; 5: 1285-1291
        • Nilsson M.
        • Unden A.B.
        • Krause D.
        • et al.
        Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.
        Proc Natl Acad Sci USA. 2000; 97: 3438-3443
        • Grachtchouk M.
        • Mo R.
        • Yu S.
        • et al.
        Basal cell carcinomas in mice overexpressing Gli2 in skin.
        Nat Genet. 2000; 24: 216-217
        • Hutchin M.E.
        • Kariapper M.S.
        • Grachtchouk M.
        • et al.
        Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumourigenesis recapitulates the hair growth cycle.
        Genes Dev. 2005; 19: 214-223
        • Berman D.M.
        • Karhadkar S.S.
        • Maitra A.
        • et al.
        Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.
        Nature. 2003; 425: 846-851
        • Karhadkar S.S.
        • Bova G.S.
        • Abdallah N.
        • et al.
        Hedgehog signalling in prostate regeneration, neoplasia and metastasis.
        Nature. 2004; 431: 707-712
        • Watkins D.N.
        • Berman D.M.
        • Burkholder S.G.
        • et al.
        Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.
        Nature. 2003; 422: 313-317
        • Thayer S.P.
        • di Magliano M.P.
        • Heiser P.W.
        • et al.
        Hedgehog is an early and late mediator of pancreatic cancer tumourigenesis.
        Nature. 2003; 425: 851-856
        • Sheng T.
        • Li C.
        • Zhang X.
        • et al.
        Activation of the hedgehog pathway in advanced prostate cancer.
        Mol Cancer. 2004; 3: 29
        • Sanchez P.
        • Hernandez A.M.
        • Stecca B.
        • et al.
        Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.
        Proc Natl Acad Sci USA. 2004; 101: 12561-12566
        • Fan L.
        • Pepicelli C.V.
        • Dibble C.C.
        • et al.
        Hedgehog signaling promotes prostate xenograft tumour growth.
        Endocrinology. 2004; 145: 3961-3970
        • Taipale J.
        • Chen J.K.
        • Cooper M.K.
        • et al.
        Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine.
        Nature. 2000; 406: 1005-1009
        • Frank-Kamenetsky M.
        • Zhang X.M.
        • Bottega S.
        • et al.
        Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.
        J Biol. 2002; 1: 10
        • Sanchez P.
        • Ruiz i Altaba A.
        In vivo inhibition of endogenous brain tumours through systemic interference of Hedgehog signaling in mice.
        Mech Dev. 2005; 122: 223-230
        • Williams J.A.
        • Guicherit O.M.
        • Zaharian B.I.
        • et al.
        Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions.
        Proc Natl Acad Sci USA. 2003; 100: 4616-4621
        • Romer J.T.
        • Kimura H.
        • Magdaleno S.
        • et al.
        Suppression of the SHH pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−) p53(−/−) mice.
        Cancer Cell. 2004; 6: 229-240
        • Athar M.
        • Li C.
        • Tang X.
        • et al.
        Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis.
        Cancer Res. 2004; 64: 7545-7552
        • Ruppert J.M.
        • Vogelstein B.
        • Kinzler K.W.
        The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A.
        Mol Cell Biol. 1991; 11: 1724-1728
        • Regl G.
        • Neill G.W.
        • Eichberger T.
        • et al.
        Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma.
        Oncogene. 2002; 21: 5529-5539
        • Kimura H.
        • Stephen D.
        • Joyner A.
        • et al.
        Gli1 is important for medulloblastoma formation in Ptc1(+/−) mice.
        Oncogene. 2005; 24: 4026-4036
        • Park H.L.
        • Bai C.
        • Platt K.A.
        • et al.
        Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.
        Development. 2000; 127: 1593-1605
        • Niemann C.
        • Unden A.B.
        • Lyle S.
        • et al.
        Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis.
        Proc Natl Acad Sci USA. 2003; 100: 11873-11880
        • St-Jacques B.
        • Dassule H.R.
        • Karavanova I.
        • et al.
        Sonic hedgehog signaling is essential for hair development.
        Curr Biol. 1998; 8: 1058-1068
        • Beachy P.A.
        • Karhadkar S.S.
        • Berman D.M.
        Tissue repair and stem cell renewal in carcinogenesis.
        Nature. 2004; 432: 324-331
        • Reya T.
        • Morrison S.J.
        • Clarke M.F.
        • et al.
        Stem cells, cancer, and cancer stem cells.
        Nature. 2001; 414: 105-111
        • Dean M.
        • Fojo T.
        • Bates S.
        Tumour stem cells and drug resistance.
        Nat Rev Cancer. 2005; 5: 275-284
        • Regl G.
        • Kasper M.
        • Schnidar H.
        • et al.
        The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells.
        Oncogene. 2004; 23: 1263-1274
        • Kenney A.M.
        • Rowitch D.H.
        Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors.
        Mol Cell Biol. 2000; 20: 9055-9067
        • Long F.
        • Zhang X.M.
        • Karp S.
        • et al.
        Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation.
        Development. 2001; 128: 5099-5108
        • Li Y.
        • Zhang H.
        • Choi S.C.
        • et al.
        Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis.
        Dev Biol. 2004; 270: 214-231
        • Yoon J.W.
        • Kita Y.
        • Frank D.J.
        • et al.
        Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation.
        J Biol Chem. 2002; 277: 5548-5555
        • Duman-Scheel M.
        • Weng L.
        • Xin S.
        • et al.
        Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E.
        Nature. 2002; 417: 299-304
        • Kenney A.M.
        • Cole M.D.
        • Rowitch D.H.
        Nmyc upregulation by Sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors.
        Development. 2003; 130: 15-28
        • Regl G.
        • Kasper M.
        • Schnidar H.
        • et al.
        Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2.
        Cancer Res. 2004; 64: 7724-7731
        • Bigelow R.L.
        • Chari N.S.
        • Unden A.B.
        • et al.
        Transcriptional regulation of bcl-2 mediated by the Sonic hedgehog signaling pathway through Gli-1.
        J Biol Chem. 2004; 279: 1197-1205
        • Louro I.D.
        • Bailey E.C.
        • Li X.
        • et al.
        Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation.
        Cancer Res. 2002; 62: 5867-5873
        • van den Heuvel M.
        • Ingham P.W.
        Smoothened encodes a receptor-like serpentine protein required for hedgehog signalling.
        Nature. 1996; 382: 547-551
        • Zhang X.M.
        • Ramalho-Santos M.
        • McMahon A.P.
        Smoothened mutants reveal redundant roles for SHH and IHH signaling including regulation of L/R symmetry by the mouse node.
        Cell. 2001; 106: 781-792
        • Soutschek J.
        • Akinc A.
        • Bramlage B.
        • et al.
        Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.
        Nature. 2004; 432: 173-178
        • Song E.
        • Zhu P.
        • Lee S.K.
        • et al.
        Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.
        Nat Biotechnol. 2005; 23: 709-717
        • Tay S.Y.
        • Ingham P.W.
        • Roy S.
        A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo.
        Development. 2005; 132: 625-634