title: Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways.
abstract: Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways.
authors.affiliation: Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, UK.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Sharov
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Mardaryev
authors.forename: Tatyana Y
authors.initials: TY
authors.lastname: Sharova
authors.forename: Marina
authors.initials: M
authors.lastname: Grachtchouk
authors.forename: Ruzanna
authors.initials: R
authors.lastname: Atoyan
authors.forename: H Randolph
authors.initials: HR
authors.lastname: Byers
authors.forename: John T
authors.initials: JT
authors.lastname: Seykora
authors.forename: Paul
authors.initials: P
authors.lastname: Overbeek
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dlugosz
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Botchkarev
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D005260:Female; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D053823:Hedgehog Proteins; D051153:Wnt Proteins; D000099176:Noggin Protein; C509239:SHH protein, human; C465570:Shh protein, mouse
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14842-7
references.pmid: 17003113
references.citation: Front Biosci. 2006 Sep 01;11:2093-105
references.pmid: 16720296
references.citation: Biochem Biophys Res Commun. 2004 Oct 8;323(1):229-34
references.pmid: 15351726
references.citation: Gastroenterology. 2007 Sep;133(3):937-50
references.pmid: 17673212
references.citation: Oncogene. 2006 Jan 12;25(2):207-17
references.pmid: 16170355
references.citation: Science. 2004 Mar 12;303(5664):1684-6
references.pmid: 15017003
references.citation: J Invest Dermatol. 2003 Jan;120(1):36-47
references.pmid: 12535196
references.citation: Exp Dermatol. 2006 Sep;15(9):667-77
references.pmid: 16881963
references.citation: Nat Cell Biol. 1999 Jul;1(3):158-64
references.pmid: 10559902
references.citation: J Biol Chem. 2000 Mar 3;275(9):6075-9
references.pmid: 10692396
references.citation: FASEB J. 2001 Oct;15(12):2205-14
references.pmid: 11641247
references.citation: Mol Carcinog. 2006 Jun;45(6):389-96
references.pmid: 16673381
references.citation: Nature. 2008 Apr 3;452(7187):650-3
references.pmid: 18385740
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):93-8
references.pmid: 15618398
references.citation: Development. 2004 Apr;131(8):1825-33
references.pmid: 15084466
references.citation: Development. 2004 May;131(10):2257-68
references.pmid: 15102710
references.citation: Nat Biotechnol. 2004 Apr;22(4):411-7
references.pmid: 15024388
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9075-80
references.pmid: 16769906
references.citation: EMBO J. 2003 Jun 16;22(12):2992-3003
references.pmid: 12805214
references.citation: Cell. 1998 Nov 25;95(5):605-14
references.pmid: 9845363
references.citation: Science. 2006 Jun 30;312(5782):1946-9
references.pmid: 16809539
references.citation: Dev Biol. 2004 Apr 1;268(1):185-94
references.pmid: 15031115
references.citation: Stem Cells. 2006 Dec;24(12):2826-39
references.pmid: 16960130
references.citation: Development. 2007 Jan;134(1):117-25
references.pmid: 17164417
references.citation: Nature. 2007 Feb 22;445(7130):834-42
references.pmid: 17314969
references.citation: Nat Med. 2006 Apr;12(4):395-7
references.pmid: 16565724
references.citation: Cancer Biol Ther. 2002 Nov-Dec;1(6):621-5
references.pmid: 12642683
references.citation: Cancer Res. 2005 Oct 1;65(19):8671-8
references.pmid: 16204035
references.citation: Carcinogenesis. 1993 Nov;14(11):2353-8
references.pmid: 8242866
references.citation: J Cell Biol. 2003 Nov 10;163(3):609-23
references.pmid: 14610062
references.citation: J Invest Dermatol. 2008 Apr;128(4):783-90
references.pmid: 18337711
references.citation: Teratog Carcinog Mutagen. 1995;15(1):11-21
references.pmid: 7604388
references.citation: PLoS One. 2008 Jan 23;3(1):e1483
references.pmid: 18213391
references.citation: Science. 1997 May 2;276(5313):817-21
references.pmid: 9115210
references.citation: Bioinformatics. 2005 May 15;21(10):2548-9
references.pmid: 15734774
references.citation: Cell. 2004 Sep 3;118(5):635-48
references.pmid: 15339667
references.citation: Am J Pathol. 2004 Mar;164(3):1099-114
references.pmid: 14982863
references.citation: Mol Carcinog. 2007 Aug;46(8):660-4
references.pmid: 17477360
references.citation: Development. 2004 Apr;131(8):1787-99
references.pmid: 15084463
references.citation: Cytokine Growth Factor Rev. 2005 Jun;16(3):251-63
references.pmid: 15871923
references.citation: Genes Dev. 2005 Jan 15;19(2):214-23
references.pmid: 15625189
references.citation: Nat Genet. 2000 Mar;24(3):216-7
references.pmid: 10700170
references.citation: Genes Dev. 2008 Feb 15;22(4):543-57
references.pmid: 18281466
references.citation: Nat Genet. 2008 Sep;40(9):1130-5
references.pmid: 19165927
references.citation: Semin Cancer Biol. 2005 Apr;15(2):75-83
references.pmid: 15652452
references.citation: Genesis. 2004 May;39(1):10-25
references.pmid: 15124223
references.citation: Oncogene. 2001 Jan 25;20(4):471-83
references.pmid: 11313978
references.citation: Biochim Biophys Acta. 1998 Dec 22;1443(3):358-63
references.pmid: 9878825
references.citation: Development. 2002 Jan;129(1):95-109
references.pmid: 11782404
references.citation: Stem Cell Rev. 2007 Jan;3(1):30-8
references.pmid: 17873379
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18166-71
references.pmid: 17114283
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10063-8
references.pmid: 17553962
references.citation: J Cell Biol. 1996 Oct;135(1):227-39
references.pmid: 8858176
references.citation: Nat Rev Cancer. 2003 Jun;3(6):444-51
references.pmid: 12778134