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Title: TIME-SENSITIVE REVERSAL OF HYPERPLASIA IN TRANSGENIC MICE EXPRESSING SV40 T ANTIGEN.

Author
item EWALD, DAGMAR - NIH
item LI, MINGLIN - UM MEDICAL SCHOOL
item EFRAT, SHIMON - ALBERT EINSTEIN COLLEGE
item AUER, GERT - KAROLINSKA INSTITUTE
item WALL, ROBERT
item FURTH, PRISCILLA - UM MEDICAL SCHOOL
item HENNIGHAUSEN, LOTHAR - NIH

Submitted to: Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/6/1996
Publication Date: N/A
Citation: N/A

Interpretive Summary: Genetic engineering has the potential of rapidly improving genetic characteristics of livestock. However the technology is limited by the inability to precisely control both the level and developmental timing of transgene expression. Consequently it is not possible to ask for some fundamental questions regarding the role of gene regulation during develop ment. This lack of control has also inhibited our ability to enhance growt in livestock. If a means were available to turn the newly introduced gene on and off, the constraint would be eliminated. We have recently developed such a system. The system is based on introduction of two gene constructs, one that directs transactivator gene expression to the tissue(s) of choice and the other that is responsive to the transactivator protein in the absence of tetracycline. When tetracycline is administered the transgene system is "turned off." In this report we extended our previous finding by testing our "switch" in secretory tissues, the submandibular gland. The responsive gene, T antigen, was selected because its expression normally causes tissue hyperplasia, an easily detected morphological change. Transgenic mice were produced, and by 4 months of age the hyperplastic phenotype could be detected. When tetracycline was administered for 3 weeks the hyperplastic phenotype was reversed and the cells of the submandibular gland looked normal. At 7 months of age the phenotype was not reversible. These findings demonstrate for the first time that a transgene can successfully be turned on and off resulting in the reversible control of a phenotype.

Technical Abstract: The role of viral oncoprotein expression in the maintenance of cellular transformation was examined as a function of time through controlled expression of SV40 T antigen (Tag). Expression of Tag in the submandibular gland of transgenic mice from the time of birth induced cellular transformation and extensive ductal hyperplasia by 4 months of age. The hyperplasia was reversed when Tag expression was silenced for 3 weeks. When Tag expression was silenced after 7 months, however, the hyperplasia persisted, even though Tag was absent. While the polyploidy of ductal cells could be reversed at 4 months of age, cells at 7 months of age remained polyploid even in the absence of Tag. These results support a model of time-dependent multistep tumorigenesis in which virally-transformed cells eventually lose their dependence on the viral oncoprotein for maintenance of the transformed state.