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PMID: 16880536 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes.

Molecular and cellular biology ·Vol. 26 ·No. 16 ·2006-08-00 ·Pages 6283-98

Kasper M, Schnidar H, Neill GW, Hanneder M, Klingler S, Blaas L, Schmid C, Hauser-Kronberger C, Regl G, Philpott MP, Aberger F

Abstract

Hedgehog (HH)/GLI signaling plays a critical role in epidermal development and basal cell carcinoma. Here, we provide evidence that epidermal growth factor receptor (EGFR) signaling modulates the target gene expression profile of GLI transcription factors in epidermal cells. Using expression profiling and quantitative reverse transcriptase PCR, we identified a set of 19 genes whose transcription is synergistically induced by GLI1 and parallel EGF treatment. Promoter studies of a subset of GLI/EGF-regulated genes, including the genes encoding interleukin-1 antagonist IL1R2, Jagged 2, cyclin D1, S100A7, and S100A9, suggest convergence of EGFR and HH/GLI signaling at the level of promoters of selected direct GLI target genes. Inhibition of EGFR and MEK/ERK but not of phosphatidylinositol 3-kinase/AKT abrogated synergistic activation of GLI/EGF target genes, showing that EGFR can signal via RAF/MEK/ERK to cooperate with GLI proteins in selective target gene regulation. Coexpression of the GLI/EGF target IL1R2, EGFR, and activated ERK1/2 in human anagen hair follicles argues for a cooperative role of EGFR and HH/GLI signaling in specifying the fate of outer root sheath (ORS) cells. We also show that EGF treatment neutralizes GLI-mediated induction of epidermal stem cell marker expression and provide evidence that EGFR signaling is essential for GLI-induced cell cycle progression in epidermal cells. The results suggest that EGFR signaling modulates GLI target gene profiles which may play an important regulatory role in ORS specification, hair growth, and possibly cancer.

MeSH Terms
Binding Sites/genetics Cell Proliferation Cells, Cultured Epidermal Growth Factor/pharmacology ErbB Receptors/metabolism Extracellular Signal-Regulated MAP Kinases/metabolism Gene Expression Regulation/drug effects Hair Follicle/cytology Hedgehog Proteins Humans Keratinocytes/cytology,drug effects Promoter Regions, Genetic/genetics RNA, Messenger/genetics,metabolism Receptors, Interleukin-1/metabolism Receptors, Interleukin-1 Type II Signal Transduction/drug effects Stem Cells/cytology Trans-Activators/metabolism Transcription Factors/genetics,metabolism Zinc Finger Protein GLI1
Chemicals
GLI1 protein, human Hedgehog Proteins IL1R2 protein, human RNA, Messenger Receptors, Interleukin-1 Receptors, Interleukin-1 Type II Trans-Activators Transcription Factors Zinc Finger Protein GLI1 Epidermal Growth Factor ErbB Receptors Extracellular Signal-Regulated MAP Kinases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kasper Maria
Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria.
Schnidar Harald
Neill Graham W
Hanneder Michaela
Klingler Stefan
Blaas Leander
Schmid Carmen
Hauser-Kronberger Cornelia
Regl Gerhard
Philpott Michael P
Aberger Fritz
References (113)
113 references, click to expand
  1. Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
    Cell. 1997 Jun 27;89(7):1043-53 PMID: 9215627
  2. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.
    Nature. 1997 Oct 23;389(6653):876-81 PMID: 9349822
  3. The potential role of cytokines and T cells in alopecia areata.
    J Investig Dermatol Symp Proc. 1999 Dec;4(3):235-8 PMID: 10674373
  4. Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype.
    J Investig Dermatol Symp Proc. 1999 Dec;4(3):296-301 PMID: 10674385
  5. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism.
    Dev Cell. 2004 Apr;6(4):551-62 PMID: 15068794
  6. Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site.
    Gene. 2004 Apr 14;330:101-14 PMID: 15087129
  7. FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma.
    J Invest Dermatol. 2004 May;122(5):1180-7 PMID: 15140221
  8. GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter.
    J Invest Dermatol. 2004 Jun;122(6):1503-9 PMID: 15175043
  9. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex.
    Development. 2004 Jan;131(2):337-45 PMID: 14681189
  10. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1.
    J Biol Chem. 2004 Jan 9;279(2):1197-205 PMID: 14555646
  11. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3.
    Dev Cell. 2004 Jan;6(1):103-15 PMID: 14723851
  12. Defining the epithelial stem cell niche in skin.
    Science. 2004 Jan 16;303(5656):359-63 PMID: 14671312
  13. Hedgehog signalling in cancer formation and maintenance.
    Nat Rev Cancer. 2003 Dec;3(12):903-11 PMID: 14737121
  14. ErbB receptors: directing key signaling networks throughout life.
    Annu Rev Pharmacol Toxicol. 2004;44:195-217 PMID: 14744244
  15. Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice.
    Cancer Res. 2004 Feb 1;64(3):934-41 PMID: 14871823
  16. The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells.
    Oncogene. 2004 Feb 12;23(6):1263-74 PMID: 14691458
  17. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors.
    Development. 2004 Mar;131(6):1289-98 PMID: 14960493
  18. Capturing and profiling adult hair follicle stem cells.
    Nat Biotechnol. 2004 Apr;22(4):411-7 PMID: 15024388
  19. The Hedgehog response network: sensors, switches, and routers.
    Science. 2004 Jun 18;304(5678):1755-9 PMID: 15205520
  20. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.
    Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12561-6 PMID: 15314219
  21. Hedgehog signalling in prostate regeneration, neoplasia and metastasis.
    Nature. 2004 Oct 7;431(7009):707-12 PMID: 15361885
  22. Signaling pathways in intestinal development and cancer.
    Annu Rev Cell Dev Biol. 2004;20:695-723 PMID: 15473857
  23. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line.
    J Cell Biol. 1988 Mar;106(3):761-71 PMID: 2450098
  24. The GLI gene is a member of the Kruppel family of zinc finger proteins.
    Nature. 1988 Mar 24;332(6162):371-4 PMID: 2832761
  25. The GLI gene encodes a nuclear protein which binds specific sequences in the human genome.
    Mol Cell Biol. 1990 Feb;10(2):634-42 PMID: 2105456
  26. The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A.
    Mol Cell Biol. 1991 Mar;11(3):1724-8 PMID: 1825351
  27. Cilia and Hedgehog responsiveness in the mouse.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11325-30 PMID: 16061793
  28. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway.
    J Invest Dermatol. 2005 Oct;125(4):638-46 PMID: 16185261
  29. Protein kinase C-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling.
    Cancer Res. 2006 Jan 15;66(2):839-45 PMID: 16424016
  30. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells.
    Int J Cancer. 2006 Feb 15;118(4):1022-31 PMID: 16108016
  31. Dual degradation signals control Gli protein stability and tumor formation.
    Genes Dev. 2006 Feb 1;20(3):276-81 PMID: 16421275
  32. GLI transcription factors: mediators of oncogenic Hedgehog signalling.
    Eur J Cancer. 2006 Mar;42(4):437-45 PMID: 16406505
  33. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling.
    Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4505-10 PMID: 16537363
  34. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation.
    Mol Cell Biol. 2006 May;26(9):3365-77 PMID: 16611981
  35. Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes.
    Genomics. 2006 May;87(5):616-32 PMID: 16434164
  36. Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase.
    J Biol Chem. 2006 Jul 14;281(28):19320-6 PMID: 16651270
  37. IL-1 alpha inhibits human hair follicle growth and hair fiber production in whole-organ cultures.
    Lymphokine Cytokine Res. 1993 Aug;12(4):197-203 PMID: 8218592
  38. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.
    Development. 2000 Apr;127(8):1593-605 PMID: 10725236
  39. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3438-43 PMID: 10725363
  40. Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters.
    Curr Biol. 2000 May 4;10(9):491-500 PMID: 10801437
  41. The EGF receptor: a nexus for trafficking and signaling.
    Bioessays. 2000 Aug;22(8):697-707 PMID: 10918300
  42. Enrichment for murine keratinocyte stem cells based on cell surface phenotype.
    Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10960-5 PMID: 11005869
  43. Signaling networks: the origins of cellular multitasking.
    Cell. 2000 Oct 13;103(2):193-200 PMID: 11057893
  44. Cell signaling by receptor tyrosine kinases.
    Cell. 2000 Oct 13;103(2):211-25 PMID: 11057895
  45. Effects of interleukins, colony-stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata.
    Br J Dermatol. 1996 Dec;135(6):942-8 PMID: 8977716
  46. 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. 1997 Apr;124(7):1313-22 PMID: 9118802
  47. Basal cell carcinomas in mice overexpressing sonic hedgehog.
    Science. 1997 May 2;276(5313):817-21 PMID: 9115210
  48. Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.
    Am J Pathol. 1997 Jun;150(6):1959-75 PMID: 9176390
  49. Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog.
    Nat Med. 1997 Jul;3(7):788-92 PMID: 9212109
  50. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.
    Science. 1993 Jul 23;261(5120):472-5 PMID: 8332913
  51. Effects of EGF on the morphology and patterns of DNA synthesis in isolated human hair follicles.
    J Invest Dermatol. 1994 Feb;102(2):186-91 PMID: 8106747
  52. Epidermal growth factor-related peptides and their receptors in human malignancies.
    Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232 PMID: 7612182
  53. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.
    Science. 1995 Jul 14;269(5221):230-4 PMID: 7618084
  54. Strain-dependent epithelial defects in mice lacking the EGF receptor.
    Science. 1995 Jul 14;269(5221):234-8 PMID: 7618085
  55. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor.
    Nature. 1995 Jul 27;376(6538):337-41 PMID: 7630400
  56. A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth.
    Curr Biol. 1995 Jul 1;5(7):797-806 PMID: 7583127
  57. Human homolog of patched, a candidate gene for the basal cell nevus syndrome.
    Science. 1996 Jun 14;272(5268):1668-71 PMID: 8658145
  58. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.
    Cell. 1996 Jun 14;85(6):841-51 PMID: 8681379
  59. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.
    Nat Genet. 1996 Sep;14(1):78-81 PMID: 8782823
  60. Activating Smoothened mutations in sporadic basal-cell carcinoma.
    Nature. 1998 Jan 1;391(6662):90-2 PMID: 9422511
  61. Cloning of novel isoforms of the human Gli2 oncogene and their activities to enhance tax-dependent transcription of the human T-cell leukemia virus type 1 genome.
    J Virol. 1998 May;72(5):3958-64 PMID: 9557682
  62. Sonic hedgehog signaling is essential for hair development.
    Curr Biol. 1998 Sep 24;8(19):1058-68 PMID: 9768360
  63. Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation.
    Nat Biotechnol. 1998 Oct;16(10):939-45 PMID: 9788350
  64. The Notch signalling pathway in hair growth.
    Mech Dev. 1998 Nov;78(1-2):189-92 PMID: 9858728
  65. Essential role for Sonic hedgehog during hair follicle morphogenesis.
    Dev Biol. 1999 Jan 1;205(1):1-9 PMID: 9882493
  66. A frequent activated smoothened mutation in sporadic basal cell carcinomas.
    Oncogene. 1999 Jan 21;18(3):833-6 PMID: 9989836
  67. Overcoming expression and purification problems of RhoGDI using a family of "parallel" expression vectors.
    Protein Expr Purif. 1999 Feb;15(1):34-9 PMID: 10024467
  68. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3.
    J Biol Chem. 1999 Mar 19;274(12):8143-52 PMID: 10075717
  69. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization.
    Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2880-4 PMID: 10077605
  70. Gli proteins encode context-dependent positive and negative functions: implications for development and disease.
    Development. 1999 Jun;126(14):3205-16 PMID: 10375510
  71. 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 Sep;126(17):3915-24 PMID: 10433919
  72. Gli1 protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells in normal human skin.
    J Invest Dermatol. 1999 Oct;113(4):595-9 PMID: 10504446
  73. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2.
    Cancer Res. 2004 Nov 1;64(21):7724-31 PMID: 15520176
  74. MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription.
    Genes Dev. 2004 Nov 15;18(22):2724-9 PMID: 15545630
  75. Tissue repair and stem cell renewal in carcinogenesis.
    Nature. 2004 Nov 18;432(7015):324-31 PMID: 15549094
  76. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain.
    Development. 2005 Jan;132(2):335-44 PMID: 15604099
  77. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle.
    Genes Dev. 2005 Jan 15;19(2):214-23 PMID: 15625189
  78. Sonic hedgehog induces epidermal growth factor dependent matrix infiltration in HaCaT keratinocytes.
    J Invest Dermatol. 2005 Feb;124(2):457-65 PMID: 15675968
  79. Post-translational modifications influence transcription factor activity: a view from the ETS superfamily.
    Bioessays. 2005 Mar;27(3):285-98 PMID: 15714552
  80. Dorsoventral patterning of the Xenopus eye: a collaboration of Retinoid, Hedgehog and FGF receptor signaling.
    Development. 2005 Apr;132(7):1737-48 PMID: 15753216
  81. Communicating with Hedgehogs.
    Nat Rev Mol Cell Biol. 2005 Apr;6(4):306-17 PMID: 15803137
  82. Therapeutic targeting of the Hedgehog-GLI pathway in prostate cancer.
    Cancer Res. 2005 Apr 15;65(8):2990-2 PMID: 15833820
  83. ERBB receptors and cancer: the complexity of targeted inhibitors.
    Nat Rev Cancer. 2005 May;5(5):341-54 PMID: 15864276
  84. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors.
    Development. 2005 Jul;132(13):3103-11 PMID: 15930098
  85. Cooperative requirement of the Gli proteins in neurogenesis.
    Development. 2005 Jul;132(14):3267-79 PMID: 15983404
  86. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2.
    Hum Mol Genet. 2005 Aug 1;14(15):2181-8 PMID: 15994174
  87. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.
    Cell. 2000 Feb 18;100(4):423-34 PMID: 10693759
  88. Basal cell carcinomas in mice overexpressing Gli2 in skin.
    Nat Genet. 2000 Mar;24(3):216-7 PMID: 10700170
  89. TGFbeta signaling in growth control, cancer, and heritable disorders.
    Cell. 2000 Oct 13;103(2):295-309 PMID: 11057902
  90. Hedgehog signalling in cancer.
    Cell Mol Life Sci. 2000 Nov;57(12):1720-31 PMID: 11130178
  91. Untangling the ErbB signalling network.
    Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37 PMID: 11252954
  92. Significance analysis of microarrays applied to the ionizing radiation response.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 PMID: 11309499
  93. Analysis of gene expression using high-density and IFN-gamma-specific low-density cDNA arrays.
    Genomics. 2001 Sep;77(1-2):50-7 PMID: 11543632
  94. Hedgehog signaling in animal development: paradigms and principles.
    Genes Dev. 2001 Dec 1;15(23):3059-87 PMID: 11731473
  95. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis.
    Development. 2001 Dec;128(24):5201-12 PMID: 11748155
  96. 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 Feb 15;277(7):5548-55 PMID: 11719506
  97. Getting under the skin of epidermal morphogenesis.
    Nat Rev Genet. 2002 Mar;3(3):199-209 PMID: 11972157
  98. Gli and hedgehog in cancer: tumours, embryos and stem cells.
    Nat Rev Cancer. 2002 May;2(5):361-72 PMID: 12044012
  99. Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma.
    Oncogene. 2002 Aug 15;21(36):5529-39 PMID: 12165851
  100. FOXM1 is a downstream target of Gli1 in basal cell carcinomas.
    Cancer Res. 2002 Aug 15;62(16):4773-80 PMID: 12183437
  101. Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1.
    J Biol Chem. 2002 Sep 20;277(38):35156-61 PMID: 12138125
  102. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway.
    Development. 2002 Oct;129(20):4753-61 PMID: 12361967
  103. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development.
    Genes Dev. 2003 Jan 15;17(2):282-94 PMID: 12533516
  104. Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells.
    Curr Biol. 2003 Feb 18;13(4):333-8 PMID: 12593800
  105. Notch1 functions as a tumor suppressor in mouse skin.
    Nat Genet. 2003 Mar;33(3):416-21 PMID: 12590261
  106. Hair cycle regulation of Hedgehog signal reception.
    Dev Biol. 2003 Mar 15;255(2):238-48 PMID: 12648487
  107. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention.
    Leukemia. 2003 Jul;17(7):1263-93 PMID: 12835716
  108. Differential expression of cyclin D1 in the human hair follicle.
    Am J Pathol. 2003 Sep;163(3):969-78 PMID: 12937137
  109. The emergent design of the neural tube: prepattern, SHH morphogen and GLI code.
    Curr Opin Genet Dev. 2003 Oct;13(5):513-21 PMID: 14550418
  110. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.
    Nature. 2003 Oct 23;425(6960):846-51 PMID: 14520411
  111. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis.
    Nature. 2003 Oct 23;425(6960):851-6 PMID: 14520413
  112. Hedgehog signalling in the mouse requires intraflagellar transport proteins.
    Nature. 2003 Nov 6;426(6962):83-7 PMID: 14603322
  113. Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction.
    Development. 2003 Dec;130(25):6233-43 PMID: 14602680
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.02317-05
Published
2006-08-00
Pages
6283-98
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1592816
Subset
IM
Grants
Austrian Science Fund FWF · P 16518 · Austria
External Links
PubMed source DOI: 10.1128/MCB.02317-05 PMC Full Text View journal details
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