SV40 enhancer and large-T antigen are instrumental in development of choroid plexus tumours in transgenic mice.
We have shown recently that choroid plexus tumours frequently develop in transgenic mice which have developed from fertilized eggs injected with DNA molecules containing both simian virus 40 (SV40) early-region genes and metallothionein (MT) fusion genes, and several lines of mice have now been established in which all of the offspring that inherit the foreign DNA succumb to these tumours at 3-5 months of age (ref. 1 and our unpublished data). Several other tissues, notably thymus and kidney, occasionally also show pathological changes. SV40 large-T antigen protein and messenger RNA are always present in affected tissues at much greater concentrations than in unaffected tissues, suggesting that SV40 early-region genes are preferentially activated in choroid plexus, thymus and kidney and that this activation frequently leads to tumorigenesis in the choroid plexus. To determine which regions of the original constructs are important for this tumorigenesis, we have now tested several derivatives and report here that the large-T antigen is sufficient, that the MT fusion gene is dispensable and that the SV40 enhancer (72-base-pair repeat region) has an important role in directing tumours to the choroid plexus. Deletion of the SV40 enhancer region alone commonly leads to peripheral neuropathy, as well as liver and pancreatic tumours, which are the subject of the accompanying paper. Evidence is presented that these pathologies may result from an enhancing effect of the MT sequences on large-T antigen genes, made possible by removal of the otherwise dominant SV40 enhancer.
Palmiter
R D
RD
Chen
H Y
HY
Messing
A
A
Brinster
R L
RL
D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D002104:Cadmium / Q000494:pharmacology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002551:Cerebral Ventricle Neoplasms / Q000382:microbiology* / Q000473:pathology; D002831:Choroid Plexus / Q000382:microbiology*; D004742:Enhancer Elements, Genetic; D005796:Genes; D005809:Genes, Regulator; D005814:Genes, Viral / Q000187:drug effects; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D010212:Papilloma / Q000382:microbiology* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics*; D013539:Simian virus 40 / Q000235:genetics* / Q000472:pathogenicity; D014764:Viral Proteins / Q000235:genetics*
D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D014764:Viral Proteins; D002104:Cadmium; D008668:Metallothionein; D011494:Protein Kinases