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The Hedgehog Signaling Pathway in Cancer

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Developmental Biology of Neoplastic Growth

Part of the book series: Progress in Molecular and Subcellular Biology ((PMSB,volume 40))

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References

  • Ahlgren SC, Bronner-Fraser M (1999) Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death. Curr Biol 9:1304–1314

    Article  PubMed  Google Scholar 

  • Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

    Article  PubMed  Google Scholar 

  • Alcedo J, Zou Y, Noll M (2000) Posttranscriptional regulation of smoothened is part of a self-correcting mechanism in the Hedgehog signaling system. Mol Cell 6:457–465

    Article  PubMed  Google Scholar 

  • Altaba A (1998) Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development 125:2203–2212

    PubMed  Google Scholar 

  • Altaba A, Stecca B, Sanchez P (2004) Hedgehog-Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 20(204):145–157

    Google Scholar 

  • Amanai K, Jiang J (2001) Distinct roles of Central missing and Dispatched in sending the Hedgehog signal. Development 128:5119–5127

    PubMed  Google Scholar 

  • Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, Epstein EH Jr (1999) Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5:1285–1291

    Article  PubMed  Google Scholar 

  • Aza-Blanc P, Lin HY, Altaba A, Kornberg TB (2000) Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities. Development 127:4293–4301

    PubMed  Google Scholar 

  • Bai CB, Auerbach W, Lee JS, Stephen D, Joyner AL (2002) Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129:4753–4761

    Article  PubMed  Google Scholar 

  • Barnes EA, Kong M, Ollendorff V, Donoghue DJ (2001) Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J 20:2214–2223

    Article  PubMed  Google Scholar 

  • Barreto DC, Gomez RS, Bale AE, Boson WL, de Marco L (2000) PTCH gene mutations in odontogenic keratocysts. J Dent Res 79:1418–1422

    PubMed  Google Scholar 

  • Basler K, Struhl G (1994) Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368:208–214

    Article  PubMed  Google Scholar 

  • Bellaiche Y, The I, Perrimon N (1998) Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394:85–88

    Article  PubMed  Google Scholar 

  • Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297:1559–1561

    Article  PubMed  Google Scholar 

  • Berman DM, Karhadkar SS, Maitra A, Montes DO, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851

    Article  PubMed  Google Scholar 

  • Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN, Bhatia M (2001) Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2:172–180

    Article  PubMed  Google Scholar 

  • Bigelow RL, Chari NS, Unden AB, Spurgers KB, Lee S, Roop DR, Toftgard R, McDonnell TJ (2004) Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem 279:1197–1205

    Article  PubMed  Google Scholar 

  • Bonifas JM, Pennypacker S, Chuang PT, McMahon AP, Williams M, Rosenthal A, De Sauvage FJ, Epstein EH Jr (2001) Activation of expression of hedgehog target genes in basal cell carcinomas. J Invest Dermatol 116:739–742

    Article  PubMed  Google Scholar 

  • Britto J, Tannahill D, Keynes R (2002) A critical role for sonic hedgehog signaling in the early expansion of the developing brain. Nat Neurosci 5:103–110

    Article  PubMed  Google Scholar 

  • Bumcrot DA, Takada R, McMahon AP (1995) Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol 15:2294–2303

    PubMed  Google Scholar 

  • Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K (1999) Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99:803–815

    Article  PubMed  Google Scholar 

  • Carlsson P, Mahlapuu M (2002) Forkhead transcription factors: key players in development and metabolism. Dev Biol 250:1–23

    Article  PubMed  Google Scholar 

  • Caspary T, Garcia-Garcia MJ, Huangfu D, Eggenschwiler JT, Wyler MR, Rakeman AS, Alcorn HL, Anderson KV (2002) Mouse dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol 12:1628–1632

    Article  PubMed  Google Scholar 

  • Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K (2001) Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293:2080–2084

    Article  PubMed  Google Scholar 

  • Chen CH, von Kessler DP, Park W, Wang B, Ma Y, Beachy PA (1999) Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98:305–316

    Article  PubMed  Google Scholar 

  • Chen JK, Taipale J, Cooper MK, Beachy PA (2002a) Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 16:2743–2748

    Article  PubMed  Google Scholar 

  • Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002b) Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99:14071–14076

    Article  PubMed  Google Scholar 

  • Chuang PT, McMahon AP (1999) Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397:617–621

    Article  PubMed  Google Scholar 

  • Chuang PT, Kawcak T, McMahon AP (2003) Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev 17:342–347

    Article  PubMed  Google Scholar 

  • Cohen MM Jr (2003) The hedgehog signaling network. Am J Med Genet 123A:5–28

    Article  Google Scholar 

  • Cooper MK, Porter JA, Young KE, Beachy PA (1998) Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280:1603–1607

    Article  PubMed  Google Scholar 

  • Couve-Privat S, Le Bret M, Traiffort E, Queille S, Coulombe J, Bouadjar B, Avril MF, Ruat M, Sarasin A, Daya-Grosjean L (2004) Functional analysis of novel sonic hedgehog gene mutations identified in basal cell carcinomas from xeroderma pigmentosum patients. Cancer Res 64:3559–3565

    Article  PubMed  Google Scholar 

  • Dahmane N, Lee J, Robins P, Heller P, Altaba A (1997) Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389:876–881

    Article  PubMed  Google Scholar 

  • Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H, Altaba A (2001) The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128:5201–5212

    PubMed  Google Scholar 

  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S (1999) Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem 19(274):8143–8152

    Article  Google Scholar 

  • Denef N, Neubuser D, Perez L, Cohen SM (2000) Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102:521–531

    Article  PubMed  Google Scholar 

  • Dick JE (2003) Breast cancer stem cells revealed. Proc Natl Acad Sci USA 100:3547–3549

    Article  PubMed  Google Scholar 

  • Duman-Scheel M, Weng L, Xin S, Du W (2002) Hedgehog regulates cell growth and proliferation by inducing cyclin D and cyclin E. Nature 417:299–304

    Article  PubMed  Google Scholar 

  • Dunaeva M, Michelson P, Kogerman P, Toftgard R (2003) Characterization of the physical interaction of Gli proteins with SUFU proteins. J Biol Chem 278:5116–5122

    Article  PubMed  Google Scholar 

  • Echelard Y, Epstein DJ, St Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417–1430

    Article  PubMed  Google Scholar 

  • Eggenschwiler JT, Espinoza E, Anderson KV (2001) Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412:194–198

    Article  PubMed  Google Scholar 

  • Eichberger T, Regl G, Ikram MS, Neill GW, Philpott MP, Aberger F, Frischauf AM (2004) FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. J Invest Dermatol 122:1180–1187

    Article  PubMed  Google Scholar 

  • Evans T, Boonchai W, Shanley S, Smyth I, Gillies S, Georgas K, Wainwright B, Chenevix-Trench G, Wicking C (2000) The spectrum of patched mutations in a collection of Australian basal cell carcinomas. Hum Mutat 16:43–48

    Article  PubMed  Google Scholar 

  • Fan H, Khavari PA (1999) Sonic hedgehog opposes epithelial cell cycle arrest. J Cell Biol 147:71–76

    Article  PubMed  Google Scholar 

  • Fan L, Pepicelli CV, Dibble CC, Catbagan W, Zarycki JL, Laciak R, Gipp J, Shaw A, Lamm ML, Munoz A, Lipinski R, Thrasher JB, Bushman W (2004) Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145:3961–3970

    Article  PubMed  Google Scholar 

  • Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang FY, Jones S, Shulok J, Rubin LL, Porter JA (2002) Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 1:10

    Article  PubMed  Google Scholar 

  • Furumoto TA, Miura N, Akasaka T, Mizutani-Koseki Y, Sudo H, Fukuda K, Maekawa M, Yuasa S, Fu Y, Moriya H, Taniguchi M, Imai K, Dahl E, Balling R, Pavlova M, Gossler A, Koseki H (1999) Notochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development. Dev Biol 210:15–29

    Article  PubMed  Google Scholar 

  • Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R (1996) The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14:78–81

    Article  PubMed  Google Scholar 

  • Gilbertson RJ (2004) Medulloblastoma: signalling a change in treatment. Lancet Oncol 5:209–218

    Article  PubMed  Google Scholar 

  • Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113

    Article  PubMed  Google Scholar 

  • Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC, Dlugosz AA (2000) Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet 24:216–217

    Article  PubMed  Google Scholar 

  • Gritli-Linde A, Lewis P, McMahon AP, Linde A (2001) The whereabouts of a morphogen: direct evidence for short-and graded long-range activity of hedgehog signaling peptides. Dev Biol 236:364–386

    Article  PubMed  Google Scholar 

  • Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841–851

    Article  PubMed  Google Scholar 

  • Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A (1998) Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4:619–622

    PubMed  Google Scholar 

  • Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, Muller U, Samson E, Quintanilla-Martinez L, Zimmer A (2000) Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem 275:28341–28344

    Article  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  Google Scholar 

  • Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183

    Article  PubMed  Google Scholar 

  • Hynes M, Stone DM, Dowd M, Pitts-Meek S, Goddard A, Gurney A, Rosenthal A (1997) Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19:15–26

    Article  PubMed  Google Scholar 

  • Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206

    Article  PubMed  Google Scholar 

  • Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P (2001) Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland. J Cell Biol 153:555–568

    PubMed  Google Scholar 

  • Incardona JP, Gaffield W, Kapur RP, Roelink H (1998) The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125:3553–3562

    PubMed  Google Scholar 

  • Incardona JP, Lee JH, Robertson CP, Enga K, Kapur RP, Roelink H (2000) Receptor-mediated endocytosis of soluble and membrane-tethered Sonic hedgehog by Patched-1. Proc Natl Acad Sci USA 97:12044–12049

    Article  PubMed  Google Scholar 

  • Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087

    Article  PubMed  Google Scholar 

  • Ingham PW, Nystedt S, Nakano Y, Brown W, Stark D, van den HM, Taylor AM (2000) Patched represses the Hedgehog signalling pathway by promoting modification of the Smoothened protein. Curr Biol 19; 10:1315–1318

    Article  PubMed  Google Scholar 

  • Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4:761–765

    Article  PubMed  Google Scholar 

  • Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP (2004) Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 18:937–951

    Article  PubMed  Google Scholar 

  • Jia J, Amanai K, Wang G, Tang J, Wang B, Jiang J (2002) Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416:548–552

    PubMed  Google Scholar 

  • Jia J, Tong C, Jiang J (2003) Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev 17:2709–2720

    Article  PubMed  Google Scholar 

  • Jiang J, Struhl G (1998) Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391:493–496

    Article  PubMed  Google Scholar 

  • Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH, Jr., Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671

    PubMed  Google Scholar 

  • Karim R, Tse G, Putti T, Scolyer R, Lee S (2004) The significance of the Wnt pathway in the pathology of human cancers. Pathology 36:120–128

    Article  PubMed  Google Scholar 

  • Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT (2002) Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129:5753–5765

    Article  PubMed  Google Scholar 

  • Kayed H, Kleeff J, Keleg S, Guo J, Ketterer K, Berberat PO, Giese N, Esposito I, Giese T, Buchler MW, Friess H (2004) Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer. Int J Cancer 110:668–676

    Article  PubMed  Google Scholar 

  • Keeler RF (1978) Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects. Lipids 13:708–715

    PubMed  Google Scholar 

  • Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20:9055–9067

    Article  PubMed  Google Scholar 

  • Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130:15–28

    Article  PubMed  Google Scholar 

  • Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ (1997) Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69:299–308

    PubMed  Google Scholar 

  • King RW (2002) Roughing up Smoothened: chemical modulators of Hedgehog signaling. J Biol 1:8

    Article  PubMed  Google Scholar 

  • Kogerman P, Grimm T, Kogerman L, Krause D, Unden AB, Sandstedt B, Toftgard R, Zaphiropoulos PG (1999) Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1:312–319

    Article  PubMed  Google Scholar 

  • Koike C, Mizutani T, Ito T, Shimizu Y, Yamamichi N, Kameda T, Michimukai E, Kitamura N, Okamoto T, Iba H (2002) Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431. Oncogene 21:2670–2678

    Article  PubMed  Google Scholar 

  • Kopper L, Hajdu M (2004) Tumor stem cells. Pathol Oncol Res 10:69–73

    PubMed  Google Scholar 

  • Koziel L, Kunath M, Kelly OG, Vortkamp A (2004) Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 6:801–813

    Article  PubMed  Google Scholar 

  • Kumamoto H, Ohki K, Ooya K (2004) Expression of Sonic hedgehog (SHH) signaling molecules in ameloblastomas. J Oral Pathol Med 33:185–190

    PubMed  Google Scholar 

  • Lai K, Kaspar BK, Gage FH, Schaffer DV (2003) Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6:21–27

    Article  PubMed  Google Scholar 

  • Lee CS, Buttitta L, Fan CM (2001) Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite. Proc Natl Acad Sci USA 98:11347–11352

    Article  PubMed  Google Scholar 

  • Lee JD, Treisman JE (2001) Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein. Curr Biol 11:1147–1152

    Article  PubMed  Google Scholar 

  • Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA (1994) Autoproteolysis in hedgehog protein biogenesis. Science 266:1528–1537

    PubMed  Google Scholar 

  • Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P, Van Lohuizen M, Marino S (2004) Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428:337–341

    PubMed  Google Scholar 

  • Lo ML, Nocini PF, Savoia A, Consolo U, Procaccini M, Zelante L, Pannone G, Bucci P, Dolci M, Bambini F, Solda P, Favia G (1999) Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 55:34–40

    Article  PubMed  Google Scholar 

  • Louro ID, Bailey EC, Li X, South LS, McKie-Bell PR, Yoder BK, Huang CC, Johnson MR, Hill AE, Johnson RL, Ruppert JM (2002) Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 62:5867–5873

    PubMed  Google Scholar 

  • Lum L, Zhang C, Oh S, Mann RK, von Kessler DP, Taipale J, Weis-Garcia F, Gong R, Wang B, Beachy PA (2003) Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell 12:1261–1274

    Article  PubMed  Google Scholar 

  • Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111:63–75

    Article  PubMed  Google Scholar 

  • Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S, Corbin JG, Gritli-Linde A, Dellovade T, Porter JA, Rubin LL, Dudek H, McMahon AP, Fishell G (2003) Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39:937–950

    Article  PubMed  Google Scholar 

  • Maesawa C, Tamura G, Iwaya T, Ogasawara S, Ishida K, Sato N, Nishizuka S, Suzuki Y, Ikeda K, Aoki K, Saito K, Satodate R (1998) Mutations in the human homologue of the Drosophila patched gene in esophageal squamous cell carcinoma. Genes Chromosomes Cancer 21:276–279

    Article  PubMed  Google Scholar 

  • Mahlapuu M, Enerback S, Carlsson P (2001) Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128:2397–2406

    PubMed  Google Scholar 

  • Mancuso M, Pazzaglia S, Tanori M, Hahn H, Merola P, Rebessi S, Atkinson MJ, Di MV, Covelli V, Saran A (2004) Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice. Cancer Res 64:934–941

    Article  PubMed  Google Scholar 

  • Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ (1996) Biochemical evidence that patched is the Hedgehog receptor. Nature 384:176–179

    Article  PubMed  Google Scholar 

  • McCarthy RA, Barth JL, Chintalapudi MR, Knaak C, Argraves WS (2002) Megalin functions as an endocytic sonic hedgehog receptor. J Biol Chem 277:25660–25667

    Article  PubMed  Google Scholar 

  • McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkowicz SB (1998) PTCH gene mutations in invasive transitional cell carcinoma of the bladder. Oncogene 17:1167–1172

    Article  PubMed  Google Scholar 

  • Methot N, Basler K (1999) Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 19(96):819–831

    Article  Google Scholar 

  • Methot N, Basler K (2000) Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 127:4001–4010

    PubMed  Google Scholar 

  • Micchelli CA, The I, Selva E, Mogila V, Perrimon N (2002) Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. Development 129:843–851

    PubMed  Google Scholar 

  • Michno K, Boras-Granic K, Mill P, Hui CC, Hamel PA (2003) Shh expression is required for embryonic hair follicle but not mammary gland development. Dev Biol 264:153–165

    Article  PubMed  Google Scholar 

  • Mill P, Mo R, Fu H, Grachtchouk M, Kim PC, Dlugosz AA, Hui CC (2003) Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev 17:282–294

    Article  PubMed  Google Scholar 

  • Miyazawa K, Himi T, Garcia V, Yamagishi H, Sato S, Ishizaki Y (2000) A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation. J Neurosci 20:5756–5763

    PubMed  Google Scholar 

  • Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967

    Article  PubMed  Google Scholar 

  • Moshiri A, Reh TA (2004) Persistent progenitors at the retinal margin of ptc+/− mice. J Neurosci 24:229–237

    Article  PubMed  Google Scholar 

  • Mullor JL, Calleja M, Capdevila J, Guerrero I (1997) Hedgehog activity, independent of decapentaplegic, participates in wing disc patterning. Development 124:1227–1237

    PubMed  Google Scholar 

  • Mullor JL, Dahmane N, Sun T, Altaba A (2001) Wnt signals are targets and mediators of Gli function. Curr Biol 11:769–773

    Article  PubMed  Google Scholar 

  • Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A, de Sauvage FJ (2000) Gli regulation by the opposing activities of fused and suppressor of fused. Nat Cell Biol 2:310–312

    Article  PubMed  Google Scholar 

  • Nakano Y, Nystedt S, Shivdasani AA, Strutt H, Thomas C, Ingham PW (2004) Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech Dev 121:507–518

    Article  PubMed  Google Scholar 

  • Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3:155–166

    Article  PubMed  Google Scholar 

  • Nilsson M, Unden AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, Toftgard R (2000) Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci USA 97:3438–3443

    Article  PubMed  Google Scholar 

  • Nishimaki H, Kasai K, Kozaki K, Takeo T, Ikeda H, Saga S, Nitta M, Itoh G (2004) A role of activated Sonic hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun 314:313–320

    Article  PubMed  Google Scholar 

  • Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801

    Article  PubMed  Google Scholar 

  • Nybakken KE, Turck CW, Robbins DJ, Bishop JM (2002) Hedgehog-stimulated phosphorylation of the kinesin-related protein Costal2 is mediated by the serine/threonine kinase fused. J Biol Chem 277:24638–24647

    Article  PubMed  Google Scholar 

  • Ogden SK, Ascano M, Jr., Stegman MA, Suber LM, Hooper JE, Robbins DJ (2003) Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr Biol 13:1998–2003

    Article  PubMed  Google Scholar 

  • Ogden SK, Ascano M, Jr., Stegman MA, Robbins DJ (2004) Regulation of Hedgehog signaling: a complex story. Biochem Pharmacol 67:805–814

    Article  PubMed  Google Scholar 

  • Ohki K, Kumamoto H, Ichinohasama R, Sato T, Takahashi N, Ooya K (2004) PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts. Int J Oral Maxillofac Surg 33:584–592

    Article  PubMed  Google Scholar 

  • Oliver TG, Wechsler-Reya RJ (2004) Getting at the root and stem of brain tumors. Neuron 42:885–888

    Article  PubMed  Google Scholar 

  • Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, Wickramasinghe R, Scott MP, Wechsler-Reya RJ (2003) Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA 100:7331–7336

    Article  PubMed  Google Scholar 

  • Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH, Jr., Scott MP (1997) Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276:817–821

    Article  PubMed  Google Scholar 

  • Pasca dM, Hebrok M (2003) Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3:903–911

    Article  PubMed  Google Scholar 

  • Pazzaglia S, Mancuso M, Atkinson MJ, Tanori M, Rebessi S, Majo VD, Covelli V, Hahn H, Saran A (2002) High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. Oncogene 21:7580–7584

    Article  PubMed  Google Scholar 

  • Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K, Taylor FR, Wang EA, Galdes A (1998) Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 273:14037–14045

    Article  PubMed  Google Scholar 

  • Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix-Trench G, Wiestler OD, Wicking C (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088

    PubMed  Google Scholar 

  • Ping XL, Ratner D, Zhang H, Wu XL, Zhang MJ, Chen FF, Silvers DN, Peacocke M, Tsou HC (2001) PTCH mutations in squamous cell carcinoma of the skin. J Invest Dermatol 116:614–616

    Article  PubMed  Google Scholar 

  • Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274:255–259

    Article  PubMed  Google Scholar 

  • Price MA, Kalderon D (2002) Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 108:823–835

    Article  PubMed  Google Scholar 

  • Qualtrough D, Buda A, Gaffield W, Williams AC, Paraskeva C (2004) Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int J Cancer 20(110):831–837

    Article  Google Scholar 

  • Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845

    PubMed  Google Scholar 

  • Rao G, Pedone CA, Coffin CM, Holland EC, Fults DW (2003) c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia 5:198–204

    PubMed  Google Scholar 

  • Rao G, Pedone CA, Valle LD, Reiss K, Holland EC, Fults DW (2004) Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 23:6156–6162

    Article  PubMed  Google Scholar 

  • Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P, Reifenberger G (1998) Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58:1798–1803

    PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  PubMed  Google Scholar 

  • Robbins DJ, Nybakken KE, Kobayashi R, Sisson JC, Bishop JM, Therond PP (1997) Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 90:225–234

    Article  PubMed  Google Scholar 

  • Rowitch DH, Jacques B, Lee SM, Flax JD, Snyder EY, McMahon AP (1999) Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J Neurosci 19:8954–8965

    PubMed  Google Scholar 

  • Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Therond PP (2003) Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Biol 5:907–913

    Article  PubMed  Google Scholar 

  • Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, Ruiz IA (2004) Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci USA 101:12561–12566

    Article  PubMed  Google Scholar 

  • Sasaki H, Hui C, Nakafuku M, Kondoh H (1997) A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124:1313–1322

    PubMed  Google Scholar 

  • Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (1999) Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126:3915–3924

    PubMed  Google Scholar 

  • Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51:1–28

    PubMed  Google Scholar 

  • Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, Martin N, Wicking C, Chenevix-Trench G (1994) Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet 50:282–290

    Article  PubMed  Google Scholar 

  • Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  Google Scholar 

  • Smyth I, Narang MA, Evans T, Heimann C, Nakamura Y, Chenevix-Trench G, Pietsch T, Wicking C, Wainwright BJ (1999) Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol Genet 8:291–297

    Article  PubMed  Google Scholar 

  • Somsel RJ, Wandinger-Ness A (2000) Rab GTPases coordinate endocytosis. J Cell Sci 113(2):183–192

    PubMed  Google Scholar 

  • Stegman MA, Goetz JA, Ascano M Jr, Ogden SK, Nybakken KE, Robbins DJ (2004) The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J Biol Chem 20(279):7064–7071

    Google Scholar 

  • Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H, Noll M, Hooper JE, de Sauvage F, Rosenthal A (1996) The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384:129–134

    Article  PubMed  Google Scholar 

  • Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, De Sauvage FJ, Rosenthal A (1999) Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. J Cell Sci 112:4437–4448

    PubMed  Google Scholar 

  • Strigini M, Cohen SM (1997) A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124:4697–4705

    PubMed  Google Scholar 

  • Tabata T, Kornberg TB (1994) Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76:89–102

    Article  PubMed  Google Scholar 

  • Tabs S, Avci O (2004) Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur J Dermatol 14:96–102

    PubMed  Google Scholar 

  • Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354

    Article  PubMed  Google Scholar 

  • Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406:1005–1009

    Article  PubMed  Google Scholar 

  • Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418:892–897

    Article  PubMed  Google Scholar 

  • Tas S, Avci O (2004) Rapid clearance of psoriatic skin lesions induced by topical cyclopamine. A preliminary proof of concept study. Dermatology 209:126–131

    Article  PubMed  Google Scholar 

  • Taylor FR., Wen D, Garber EA, Carmillo AN, Baker DP, Arduini RM, Williams KP, Weinreb PH, Rayhorn P, Hronowski X, Whitty A, Day ES, Boriack-Sjodin A, Shapiro RI, Galdes A, Pepinsky RB (2001) Enhanced potency of human Sonic hedgehog by hydrophobic modification. Biochem 40:4359–4371

    Article  Google Scholar 

  • Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310

    Article  PubMed  Google Scholar 

  • Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG (2002) FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res 62:4773–4780

    PubMed  Google Scholar 

  • Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856

    Article  PubMed  Google Scholar 

  • The I, Bellaiche Y, Perrimon N (1999) Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol Cell 4:633–639

    Article  PubMed  Google Scholar 

  • Tojo M, Mori T, Kiyosawa H, Honma Y, Tanno Y, Kanazawa KY, Yokoya S, Kaneko F, Wanaka A (1999) Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. Pathol Int 49:687–694

    Article  PubMed  Google Scholar 

  • Tojo M, Kiyosawa H, Iwatsuki K, Kaneko F (2002) Expression of a sonic hedgehog signal transducer, hedgehog-interacting protein, by human basal cell carcinoma. Br J Dermatol 146:69–73

    Article  PubMed  Google Scholar 

  • Tojo M, Kiyosawa H, Iwatsuki K, Nakamura K, Kaneko F (2003) Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma. Br J Dermatol 148:892–897

    Article  PubMed  Google Scholar 

  • Torroja C, Gorfinkiel N, Guerrero I (2004) Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction. Development 131:2395–2408

    Article  PubMed  Google Scholar 

  • Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M (1997) Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res 57:2336–2340

    PubMed  Google Scholar 

  • Van den Brink GR, Bleuming SA, Hardwick JC, Schepman BL, Offerhaus GJ, Keller JJ, Nielsen C, Gaffield W, van Deventer SJ, Roberts DJ, Peppelenbosch MP (2004) Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet 36:277–282

    Article  PubMed  Google Scholar 

  • Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA (2004) Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18:1131–1143

    Article  PubMed  Google Scholar 

  • Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, Toftgard R (1997a) Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15:361–366

    Article  PubMed  Google Scholar 

  • Vorechovsky I, Unden AB, Sandstedt B, Toftgard R, Stahle-Backdahl M (1997b) Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis. Cancer Res 57:4677–4681

    PubMed  Google Scholar 

  • Wallace VA (1999) Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448

    Article  PubMed  Google Scholar 

  • Wang B, Fallon JF, Beachy PA (2000) Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100:423–434

    Article  PubMed  Google Scholar 

  • Wang G, Wang B, Jiang J (1999) Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes Dev 13:2828–2837

    Article  PubMed  Google Scholar 

  • Wang G, Amanai K, Wang B, Jiang J (2000) Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev 14:2893–2905

    Article  PubMed  Google Scholar 

  • Wang QT, Holmgren RA (1999) The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels. Development 126:5097–5106

    PubMed  Google Scholar 

  • Wang QT, Holmgren RA (2000) Nuclear import of cubitus interruptus is regulated by hedgehog via a mechanism distinct from Ci stabilization and Ci activation. Development 127:3131–3139

    PubMed  Google Scholar 

  • Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB (2003) Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 20(422):313–317

    Article  Google Scholar 

  • Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22:103–114

    Article  PubMed  Google Scholar 

  • Weiner HL, Bakst R, Hurlbert MS, Ruggiero J, Ahn E, Lee WS, Stephen D, Zagzag D, Joyner AL, Turnbull DH (2002) Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1. Cancer Res 62:6385–6389

    PubMed  Google Scholar 

  • Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Porter JA, Rubin LL, Wang FY (2003) Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci USA 100:4616–4621

    Article  PubMed  Google Scholar 

  • Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G (1997) Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 57:2581–2585

    PubMed  Google Scholar 

  • Wu SC, Grindley J, Winnier GE, Hargett L, Hogan BL (1998) Mouse Mesenchyme forkhead 2 (Mf2): expression, DNA binding and induction by sonic hedgehog during somitogenesis. Mech Dev 70:3–13

    Article  PubMed  Google Scholar 

  • Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH Jr (1997) Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res 57:2369–2372

    PubMed  Google Scholar 

  • Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–92

    Article  PubMed  Google Scholar 

  • Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone P (2002) 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 277:5548–5555

    Article  PubMed  Google Scholar 

  • Zaphiropoulos PG, Unden AB, Rahnama F, Hollingsworth RE, Toftgard R (1999) PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas. Cancer Res 59:787–792

    PubMed  Google Scholar 

  • Zhang Y, Kalderon D (2001) Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature 410:599–604

    Article  PubMed  Google Scholar 

  • Zhao Q, Kho A, Kenney AM, Yuk DD, Kohane I, Rowitch DH (2002) Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach. Proc Natl Acad Sci USA 99:5704–5709

    Article  PubMed  Google Scholar 

  • Zhu AJ, Zheng L, Suyama K, Scott MP (2003) Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev 17:1240–1252

    Article  PubMed  Google Scholar 

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Vestergaard, J., Bak, M., Larsen, L.A. (2005). The Hedgehog Signaling Pathway in Cancer. In: Macieira-Coelho, A. (eds) Developmental Biology of Neoplastic Growth. Progress in Molecular and Subcellular Biology, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27671-8_1

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