Activation of both Wnt-1 and Fgf-3 by insertion of mouse mammary tumor virus downstream in the reverse orientation: a reappraisal of the enhancer insertion model.
In retrovirus-induced tumors, proviral DNA is commonly found next to or within a cellular proto-oncogene such that transcription of the gene is influenced by the viral promoter or enhancer. Extensive surveys of naturally occurring tumors reveal that proviruses integrated on the 3' side of the gene are usually in the same transcriptional orientation, suggesting a model in which the bidirectional viral enhancer acts primarily on the closest promoters. Here we describe a virally induced mammary tumor that appears to contradict these ideas since the Wnt-1/int-1 and Fgf-3/int-2 proto-oncogenes have both been activated by mouse mammary tumor virus (MMTV) DNA integrated 3' of the gene in the opposite transcriptional orientation. However, by cloning the relevant DNAs, we show that these are not simple proviral insertions. In the Wnt-1 locus, there is an additional LTR immediately adjacent to the 3' end of the MMTV provirus, while in Fgf-3, the provirus has sustained a deletion that removes the 5' LTR, gag, and most of pol. These structural alterations can be reconciled with the enhancer insertion model by postulating that the viral enhancer can only function if it is not transcribed.
Imperial Cancer Research Fund Laboratories, London, United Kingdom.
N
N
Clausse
D
D
Baines
R
R
Moore
S
S
Brookes
C
C
Dickson
G
G
Peters
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005069:Evaluation Studies as Topic; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors; D015750:Genes, gag / Q000235:genetics; D015751:Genes, pol / Q000235:genetics; D016679:Genome, Viral; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011533:Proviruses / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000032:analysis; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D016662:Virus Integration / Q000235:genetics; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D004279:DNA, Viral; C489197:Fgf3 protein, mouse; D051518:Fibroblast Growth Factor 3; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; C489200:fgf3 protein, zebrafish; D005346:Fibroblast Growth Factors