'Designer' tumors in mice.
We have developed and tested successfully a general method based on Cre-mediated recombination that can be used for ubiquitous or tissue-specific expression of protein products, including tumor-inducing oncoproteins. Depending on the specificity of a chosen promoter driving cre expression, tumors develop by design in bitransgenic mouse progeny derived by crossing Cre-producing mice with partners carrying a dormant oncogenic transgene (targeted into the 3' noncoding region of the cytoplasmic beta-actin locus) that becomes functional after excision of a 'floxed' DNA segment. To provide proof-of-principle, we have used as models transgenes encoding the polyomavirus middle T antigen (PVMT) and the T antigens of the SV40 early region (SVER). Cre-dependent activation of widespread SVER expression resulted in hyperplasias or invasive tumors affecting particular visceral smooth muscles, whereas Cre-dependent, mammary gland-specific expression of PVMT-induced adenocarcinomas, according to plan. Unexpectedly, we also encountered spontaneous (Cre-independent) oncogene expression occurring as a rare event, which simulates the initiation of sporadic tumors and leads to PVMT-induced hemangiomas and mammary carcinomas or SVER-induced disseminated sarcomas, thus, revealing particular tissue susceptibilities to the actions of these oncoproteins.
Politi
Katerina
K
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Kljuic
Ana
A
Szabolcs
Matthias
M
Fisher
Peter
P
Ludwig
Thomas
T
Efstratiadis
Argiris
A
D000199:Actins / Q000235:genetics; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000473:pathology; D016254:Mutagenesis, Insertional / Q000379:methods*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D019076:Transgenes
D000199:Actins; D000952:Antigens, Polyomavirus Transforming; D015513:Oncogene Proteins