Abnormal differentiation, hyperplasia and embryonic/perinatal lethality in BK5-T/t transgenic mice.
The cell-of-origin has a great impact on the types of tumors that develop and the stem/progenitor cells have long been considered main targets of malignant transformation. The SV40 (SV40-Simian Virus 40) large T and small t antigens (T/t), have been targeted to multiple-differentiated cellular compartments in transgenic mice. In most of these studies, transgenic animals develop tumors without apparent defects in animal development. In this study, we used the bovine keratin 5 (BK5) promoter to target the T/t antigens to stem/progenitor cell-containing cytokeratin 5 (CK5) cellular compartment. A transgene construct, BK5-T/t, was made and microinjected into the male pronucleus of FVB/N mouse oocytes. After implanting approximately 1700 embryos, only 7 transgenics were obtained, including 4 embryos (E9.5, E13, E15, and E20) and 3 postnatal animals, which died at P1, P2, and P18, respectively. Immunohistological analysis revealed aberrant differentiation and prominent hyperplasia in several transgenic CK5 tissues, especially the upper digestive organs (tongue, oral mucosa, esophagus, and forestomach) and epidermis, the latter of which also showed focal dysplasia. Altogether, these results indicate that constitutive expression of the T/t antigens in CK5 cellular compartment results in abnormal epithelial differentiation and leads to embryonic/perinatal animal lethality.
Chen
Xin
X
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Road 1-C, P.O. Box 389, Smithville, TX 78957, USA.
Schneider-Broussard
Robin
R
Hollowell
Debra
D
McArthur
Mark
M
Jeter
Collene R
CR
Benavides
Fernando
F
DiGiovanni
John
J
Tang
Dean G
DG
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D017209:Apoptosis; D002454:Cell Differentiation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000473:pathology*; D005786:Gene Expression Regulation; D006965:Hyperplasia / Q000378:metabolism; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D013539:Simian virus 40 / Q000235:genetics / Q000378:metabolism; D014059:Tongue / Q000378:metabolism / Q000473:pathology
D000952:Antigens, Polyomavirus Transforming; D053555:Keratin-5