Home LiteratureArticle Details
PMID: 1406654 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Transgenic overexpression of transforming growth factor alpha bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis.

Molecular and cellular biology ·Vol. 12 ·No. 10 ·1992-10-00 ·Pages 4643-53

Vassar R, Hutton ME, Fuchs E

Abstract

The induction of skin papillomas in mice can be divided into two different stages. Chemical initiation frequently elicits mutations in the Ha-ras gene, leading to the constitutive activation of ras. The second step, promotion, involves repetitive topical application of phorbol esters or wounding, leading to epidermal hyperproliferation and papilloma formation. We have found that overexpression of transforming growth factor alpha (TGF-alpha) in the basal epidermal layer of transgenic mice yielded papillomas directly upon wounding or 12-O-tetradecanoylphorbol-13-acetate treatment without the need for an initiator. Moreover, papillomas from TGF-alpha mice did not exhibit mutations in the Ha-ras gene. Interestingly, TGF-alpha acted synergistically with 12-O-tetradecanoylphorbol-13-acetate to enhance epidermal hyperproliferation. Our results demonstrate a central role for TGF-alpha overexpression in tumorigenesis and provide an important animal model for the study of skin tumorigenesis.

Related Genes
Ha-ras
MeSH Terms
Animals Base Sequence DNA, Neoplasm Disease Models, Animal Gene Amplification Gene Expression Regulation, Neoplastic Genes, ras Mice Mice, Transgenic Molecular Sequence Data Mutation Papilloma/etiology,genetics,pathology Skin Neoplasms/etiology,genetics,pathology Tetradecanoylphorbol Acetate/pharmacology Transforming Growth Factor alpha/genetics,metabolism Wounds and Injuries/complications
Chemicals
DNA, Neoplasm Transforming Growth Factor alpha Tetradecanoylphorbol Acetate
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Vassar R
Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, University of Chicago, Illinois 60637.
Hutton M E
Fuchs E
References (46)
46 references, click to expand
  1. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  2. Reversible inhibition of normal human prokeratinocyte proliferation by type beta transforming growth factor-growth inhibitor in serum-free medium.
    Cancer Res. 1986 Apr;46(4 Pt 2):2068-71 PMID: 2418960
  3. TGF alpha stimulates growth of skin papillomas by autocrine and paracrine mechanisms but does not cause neoplastic progression.
    Mol Carcinog. 1988;1(1):7-12 PMID: 2475136
  4. Activation of ras oncogenes in chemically transformed BALB/MK-2 mouse keratinocytes.
    Mol Carcinog. 1989;2(3):150-8 PMID: 2506887
  5. Stimulatory role of transforming growth factors in multistage skin carcinogenesis: possible explanation for the tumor-inducing effect of wounding in initiated NMRI mouse skin.
    Int J Cancer. 1989 May 15;43(5):915-21 PMID: 2714898
  6. Induction of transforming growth factor-alpha expression in human keratinocytes by phorbol esters.
    J Biol Chem. 1989 Mar 25;264(9):5164-71 PMID: 2925687
  7. Transforming growth factor-beta modulates the high-affinity receptors for epidermal growth factor and transforming growth factor-alpha.
    J Cell Biol. 1985 May;100(5):1508-14 PMID: 2985623
  8. v-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis.
    Cell. 1986 Aug 1;46(3):447-56 PMID: 3015415
  9. Development of murine epidermal cell lines which contain an activated rasHa oncogene and form papillomas in skin grafts on athymic nude mouse hosts.
    Cancer Res. 1988 Jan 1;48(1):165-9 PMID: 3121168
  10. Localized production of TGF-beta mRNA in tumour promoter-stimulated mouse epidermis.
    Nature. 1988 Jan 28;331(6154):363-5 PMID: 3422343
  11. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors.
    Cancer Res. 1987 Feb 1;47(3):707-12 PMID: 3467839
  12. Specific growth response of ras-transformed embryo fibroblasts to tumour promoters.
    Nature. 1985 Dec 5-11;318(6045):472-5 PMID: 4069218
  13. The study of tumor promotion in a cell culture model for mouse skin--a tissue that exhibits multistage carcinogenesis in vivo.
    Carcinog Compr Surv. 1982;7:217-30 PMID: 6121622
  14. Changes in keratin gene expression during terminal differentiation of the keratinocyte.
    Cell. 1980 Apr;19(4):1033-42 PMID: 6155214
  15. Monoclonal antibody analysis of keratin expression in epidermal diseases: a 48- and 56-kdalton keratin as molecular markers for hyperproliferative keratinocytes.
    J Cell Biol. 1984 Apr;98(4):1397-406 PMID: 6201492
  16. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas.
    Nature. 1984 Feb 16-22;307(5952):658-60 PMID: 6694757
  17. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene.
    Nature. 1983 May 5-11;303(5912):72-4 PMID: 6843661
  18. Malignant conversion of mouse skin tumours is increased by tumour initiators and unaffected by tumour promoters.
    Nature. 1983 Jul 7-13;304(5921):67-9 PMID: 6866091
  19. Cooperative stimulation of specific gene transcription by epidermal growth factor and transforming growth factor type beta 1.
    J Biol Chem. 1990 Feb 25;265(6):3001-4 PMID: 2105937
  20. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights.
    Cell. 1990 Oct 19;63(2):245-7 PMID: 2208284
  21. 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
  22. The Son of sevenless gene product: a putative activator of Ras.
    Science. 1992 Jan 31;255(5044):603-6 PMID: 1736363
  23. Altered regulation of TGF-beta 1 and TGF-alpha in primary keratinocytes and papillomas expressing v-Ha-ras.
    Mol Carcinog. 1991;4(3):210-9 PMID: 2064727
  24. Transfection of the EJ rasHa gene into keratinocytes derived from carcinogen-induced mouse papillomas causes malignant progression.
    Mol Cell Biol. 1986 Sep;6(9):3144-9 PMID: 2431297
  25. Sequence and expression of a type II keratin, K5, in human epidermal cells.
    Mol Cell Biol. 1988 Jan;8(1):486-93 PMID: 2447486
  26. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta.
    Mol Cell Biol. 1988 Aug;8(8):3088-93 PMID: 2463471
  27. Evaluation of the cocarcinogenic effect of wounding in Rous sarcoma virus tumorigenesis.
    Cancer Res. 1989 Nov 15;49(22):6419-24 PMID: 2553256
  28. Cultivation and characterization of cells derived from mouse skin papillomas induced by an initiation-promotion protocol.
    Carcinogenesis. 1986 Jun;7(6):949-58 PMID: 2871947
  29. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis.
    Nature. 1986 Jul 3-9;322(6074):78-80 PMID: 3014349
  30. Mutagenesis of the Ha-ras oncogene in mouse skin tumors induced by polycyclic aromatic hydrocarbons.
    Proc Natl Acad Sci U S A. 1986 Aug;83(16):6048-52 PMID: 3016738
  31. Chemical carcinogenesis: from animal models to molecular models in one decade.
    Adv Cancer Res. 1988;50:25-70 PMID: 3287845
  32. Transforming ras oncogenes and multistage carcinogenesis.
    Br J Cancer. 1985 Jan;51(1):1-7 PMID: 3881118
  33. Studies on the mechanism of skin tumor promotion.
    Cancer Res. 1970 Feb;30(2):312-20 PMID: 5458969
  34. The 50- and 58-kdalton keratin classes as molecular markers for stratified squamous epithelia: cell culture studies.
    J Cell Biol. 1983 Jul;97(1):244-51 PMID: 6190820
  35. Oncogene-induced transformation of C3H 10T1/2 cells is enhanced by tumor promoters.
    Science. 1984 Nov 2;226(4674):552-5 PMID: 6436974
  36. Tumor promotion by abrasion induced epidermal hyperplasia in the skin of mice.
    J Invest Dermatol. 1980 Oct;75(4):360-2 PMID: 6776204
  37. TGF-beta and retinoic acid: regulators of growth and modifiers of differentiation in human epidermal cells.
    Cell Regul. 1990 Oct;1(11):791-809 PMID: 1708287
  38. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation.
    Genes Dev. 1991 May;5(5):714-27 PMID: 1709129
  39. Regulation of p21ras activity.
    Trends Genet. 1991 Nov-Dec;7(11-12):346-51 PMID: 1820685
  40. Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression.
    Proc Natl Acad Sci U S A. 1990 Jan;87(2):538-42 PMID: 2105486
  41. Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta.
    Science. 1990 Jun 29;248(4963):1656-60 PMID: 2163544
  42. Specific effects of ras oncogene expression on the growth and histogenesis of human epidermal keratinocytes.
    Oncogene. 1990 Apr;5(4):475-81 PMID: 2183155
  43. Keratin gene expression in mouse skin tumors and in mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate.
    Cancer Res. 1985 Nov;45(11 Pt 2):5845-50 PMID: 2414001
  44. Members of the src and ras oncogene families supplant the epidermal growth factor requirement of BALB/MK-2 keratinocytes and induce distinct alterations in their terminal differentiation program.
    Mol Cell Biol. 1985 Dec;5(12):3386-96 PMID: 2427928
  45. An activated Harvey ras oncogene produces benign tumours on mouse epidermal tissue.
    Nature. 1986 Oct 30-Nov 5;323(6091):822-4 PMID: 2430189
  46. Use of monospecific antisera and cRNA probes to localize the major changes in keratin expression during normal and abnormal epidermal differentiation.
    J Cell Biol. 1988 Aug;107(2):427-46 PMID: 2458356
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.12.10.4643-4653.1992
Published
1992-10-00
Pages
4643-53
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC360391
Subset
IM
Grants
NIAMS NIH HHS · AR31737 · United States
External Links
PubMed source DOI: 10.1128/mcb.12.10.4643-4653.1992 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2