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PMID: 10725363 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 7 ·2000-03-28 ·Pages 3438-43

Nilsson M, Undèn AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, Toftgård R

Abstract

Basal cell carcinoma is the most prevalent cancer in the western world, showing a rapid increase in incidence. Activation of the Sonic hedgehog/Patched (PTCH) signaling pathway because of PTCH1 inactivation is a key event in sporadic and familial basal cell carcinoma development in humans and is associated with transcriptional activation of specific target genes, including PTCH1 itself. These changes are analogous to the situation in Drosophila where hedgehog activates the zinc-finger transcription factor Cubitus interruptus, leading to increased transcription of target genes. In the present study, we show that mice ectopically expressing the human Cubitus interruptus homolog GLI-1 in the skin develop tumors closely resembling human BCCs as well as other hair follicle-derived neoplasias, such as trichoepitheliomas, cylindromas, and trichoblastomas. Furthermore, examination of the tumors revealed wild-type p53 and Ha ras genes. These findings firmly establish that increased GLI-1 expression is central and probably sufficient for tumor development and suggest that GLI-1-induced tumor development does not depend on additional p53 or Ha ras mutations.

MeSH Terms
Animals Base Sequence Carcinoma, Basal Cell/genetics DNA Primers Genes, p53 Genes, ras Humans Kruppel-Like Transcription Factors Mice Mice, Transgenic Skin/metabolism Skin Neoplasms/genetics Transcription Factors/genetics Zinc Finger Protein GLI1
Chemicals
DNA Primers GLI1 protein, human Gli1 protein, mouse Kruppel-Like Transcription Factors Transcription Factors Zinc Finger Protein GLI1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Nilsson M
Department of Biosciences at Novum, Karolinska Institutet, SE-141 57, Huddinge, Sweden.
Undèn A B
Krause D
Malmqwist U
Raza K
Zaphiropoulos P G
Toftgård R
References (47)
47 references, click to expand
  1. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1.
    Nat Cell Biol. 1999 Sep;1(5):312-9 PMID: 10559945
  2. Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle.
    Development. 1999 Jun;126(12):2611-21 PMID: 10331973
  3. The GLI gene is a member of the Kruppel family of zinc finger proteins.
    Nature. 1988 Mar 24;332(6162):371-4 PMID: 2832761
  4. The GLI-Kruppel family of human genes.
    Mol Cell Biol. 1988 Aug;8(8):3104-13 PMID: 2850480
  5. Deletion of the c-Ha-ras-1 allele in human skin cancers.
    Mol Carcinog. 1989;2(5):298-301 PMID: 2690853
  6. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter.
    Cell. 1990 Aug 24;62(4):697-708 PMID: 1696852
  7. The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A.
    Mol Cell Biol. 1991 Mar;11(3):1724-8 PMID: 1825351
  8. p53 mutations in human cancers.
    Science. 1991 Jul 5;253(5015):49-53 PMID: 1905840
  9. Ras gene mutation and amplification in human nonmelanoma skin cancers.
    Mol Carcinog. 1991;4(3):196-202 PMID: 2064725
  10. Keratin expression in basal cell carcinomas.
    Br J Dermatol. 1992 Feb;126(2):154-60 PMID: 1371396
  11. Occurrence of basal cell carcinoma among multiple trichoepitheliomas.
    J Am Acad Dermatol. 1993 Feb;28(2 Pt 2):322-6 PMID: 8436650
  12. Ras proto-oncogene activation in liver and lung tumors from B6C3F1 mice exposed chronically to methylene chloride.
    Carcinogenesis. 1993 May;14(5):795-801 PMID: 8504471
  13. Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice.
    Carcinogenesis. 1993 May;14(5):803-10 PMID: 8504472
  14. Sequences 5' of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development.
    Differentiation. 1994 Nov;58(1):53-64 PMID: 7532601
  15. Human homolog of patched, a candidate gene for the basal cell nevus syndrome.
    Science. 1996 Jun 14;272(5268):1668-71 PMID: 8658145
  16. 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
  17. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal.
    Cell. 1996 Jul 26;86(2):221-32 PMID: 8706127
  18. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.
    Nat Genet. 1996 Sep;14(1):78-81 PMID: 8782823
  19. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog.
    Nature. 1996 Nov 14;384(6605):129-34 PMID: 8906787
  20. Biochemical evidence that patched is the Hedgehog receptor.
    Nature. 1996 Nov 14;384(6605):176-9 PMID: 8906794
  21. LIFE HISTORY OF ORGANOID NEVI. SPECIAL REFERENCE TO NEVUS SEBACEUS OF JADASSOHN.
    Arch Dermatol. 1965 Jun;91:574-88 PMID: 14295518
  22. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.
    Nat Med. 1999 Nov;5(11):1285-91 PMID: 10545995
  23. Frequent clones of p53-mutated keratinocytes in normal human skin.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14025-9 PMID: 8943054
  24. Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development.
    Dev Biol. 1996 Nov 25;180(1):273-83 PMID: 8948590
  25. 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
  26. Basal cell carcinomas in mice overexpressing sonic hedgehog.
    Science. 1997 May 2;276(5313):817-21 PMID: 9115210
  27. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.
    Cancer Res. 1997 Jun 15;57(12):2336-40 PMID: 9192803
  28. Catching a Gli-mpse of Hedgehog.
    Cell. 1997 Jul 25;90(2):193-6 PMID: 9244291
  29. Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1.
    Neuron. 1997 Jul;19(1):15-26 PMID: 9247260
  30. Altered neural cell fates and medulloblastoma in mouse patched mutants.
    Science. 1997 Aug 22;277(5329):1109-13 PMID: 9262482
  31. Molecular pathology in basal cell cancer with p53 as a genetic marker.
    Oncogene. 1997 Aug 28;15(9):1059-67 PMID: 9285560
  32. 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
  33. Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis.
    Cancer Res. 1997 Nov 1;57(21):4677-81 PMID: 9354420
  34. Activating Smoothened mutations in sporadic basal-cell carcinoma.
    Nature. 1998 Jan 1;391(6662):90-2 PMID: 9422511
  35. Brooke-Spiegler syndrome variant: segregation of tumor types with mixed differentiation in two generations.
    Am J Dermatopathol. 1998 Feb;20(1):56-60 PMID: 9504671
  36. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome.
    Nat Med. 1998 May;4(5):619-22 PMID: 9585239
  37. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome.
    J Invest Dermatol. 1998 Jun;110(6):885-8 PMID: 9620294
  38. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice.
    Development. 1998 Jul;125(14):2533-43 PMID: 9636069
  39. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system.
    Development. 1998 Aug;125(15):2759-70 PMID: 9655799
  40. Sonic hedgehog signaling is essential for hair development.
    Curr Biol. 1998 Sep 24;8(19):1058-68 PMID: 9768360
  41. Familial cylindromatosis mimicking tuberous sclerosis complex and confirmation of the cylindromatosis locus, CYLD1, in a large family.
    J Med Genet. 1998 Oct;35(10):841-5 PMID: 9783709
  42. Essential role for Sonic hedgehog during hair follicle morphogenesis.
    Dev Biol. 1999 Jan 1;205(1):1-9 PMID: 9882493
  43. Basal cell carcinoma development is associated with induction of the expression of the transcription factor Gli-1.
    Br J Dermatol. 1998 Nov;139(5):911-5 PMID: 9892966
  44. Sonic hedgehog signaling by the patched-smoothened receptor complex.
    Curr Biol. 1999 Jan 28;9(2):76-84 PMID: 10021362
  45. The sebaceous nevus: a nevus with deletions of the PTCH gene.
    Cancer Res. 1999 Apr 15;59(8):1834-6 PMID: 10213487
  46. Cytokeratin expression in trichoblastic fibroma (small nodular type trichoblastoma), trichoepithelioma and basal cell carcinoma.
    Br J Dermatol. 1999 Jan;140(1):8-16 PMID: 10215762
  47. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.050467397
Published
2000-03-28
Pages
3438-43
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC16258
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.050467397 PMC Full Text View journal details
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