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Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice

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Abstract

AVIAN sarcoma virus 17 induces fibrosarcomas in chickens1 and can transform a number of avian cell types in vitro2 by the action of v-jun (refs 1–3). This gene and the related cellular genes c-jun4–6, jun B7 and jun D8,9, encode transactivating (or repressing) DNA-binding proteins that form homo- or heterodimeric (Jun–Jun and Jun–Fos) complexes5,10,11 which recognize the AP-1 consensus sequence TGACTCA (refs 12,13), a response element that confers sensitivity to the tumour-promoting phorbol ester TPA14. We have produced several lines of transgenic mice carrying the v-jun oncogene, driven by the promoter of the widely expressed H-2Kk major histocompatibility complex (MHC) class I antigen gene. Transgenic animals are initially phenotypically normal, but after full-thickness wounding they show abnormal wound repair, characterized by hyperplastic granulation tissue. Many of these lesions are slowly progressive because of continuing fibrob blast proliferation, and over 2–5 months some give rise to dermal fibrosarcomas. This reproducible multistep transition through a proliferative but benign intermediate is associated with characteristic increments in v-jun expression. Moreover, hyperplastic wound repair and its progression are both related to transgene dosage, suggesting that there exists a quantitative requirement or threshold for v-jun action. Our results indicate that v-jun is not oncogenic in transgenic mice as a result of a 'single-hit' mechanism, but rather, in addition to an obligatory wound, that secondary genetic or epigenetic events (possibly conscripting normal constituents of wound repair) are necessary for tumour development and progression.

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Authors and Affiliations

  1. Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute,

    Andre C. Schuh & Martin L. Breitman

  2. Department of Pathology, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G1X5

    Sarah J. Keating

  3. Canada Department of Pathology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

    Sarah J. Keating

  4. Canada Department of Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

    Martin L. Breitman

  5. Department of Microbiology, USC School of Medicine, Los Angeles, California, 90033-1054, USA

    Felipe S. Monteclaro & Peter K. Vogt

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  1. Andre C. Schuh
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  2. Sarah J. Keating
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  3. Felipe S. Monteclaro
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  4. Peter K. Vogt
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  5. Martin L. Breitman
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Schuh, A., Keating, S., Monteclaro, F. et al. Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice. Nature 346, 756–760 (1990). https://doi.org/10.1038/346756a0

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