Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice.
Avian sarcoma virus 17 induces fibrosarcomas in chickens and can transform a number of avian cell types in vitro by the action of v-jun. This gene and the related cellular genes c-jun, jun B and jun D, encode transactivating (or repressing) DNA-binding proteins that form homo- or heterodimeric (Jun-Jun and Jun-Fos) complexes which recognize the AP-1 consensus sequence TGACTCA, a response element that confers sensitivity to the tumour-promoting phorbol ester TPA. 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 fibroblast 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.
Schuh
A C
AC
Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.
Keating
S J
SJ
Monteclaro
F S
FS
Vogt
P K
PK
Breitman
M L
ML
D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics; D015152:Blotting, Northern; D002460:Cell Line; D005354:Fibrosarcoma / Q000235:genetics* / Q000473:pathology; D005805:Genes, MHC Class I; D051379:Mice; D008822:Mice, Transgenic; D016759:Oncogene Protein p65(gag-jun); D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics*; D014158:Transcription, Genetic; D014947:Wounds and Injuries / Q000473:pathology*
D016759:Oncogene Protein p65(gag-jun); D012333:RNA, Messenger; D015682:Retroviridae Proteins, Oncogenic; D011505:Protein-Tyrosine Kinases