Targeted oncogenesis in transgenic mice has unexpectedly produced predictable tissue-specific tumors. We previously showed that hybrid gene constructs of the human fetal Gγ- or mouse embryonic βh1-globin promoter linked to the viral simian virus 40 T antigen (Gγ/T and βh1/T) expressed appropriately in embryonic erythroid tissue, with some unexpected expression elsewhere. Tumors arising in the Gγ/T and βh1/T transgenic mice were identified by histology, electron microscopy, cell culture, and RNase protection analyses. In one Gγ/T transgenic line, males developed prostate tumors that showed mixed neuroendocrine and epithelial cell features, whereas females developed adrenocortical tumors. In several other Gγ/T lines, brown adipose tumors, or hibernomas, developed in the subcutaneous interscapular neck and shoulder area, as well as internally in the periadrenal and pericardial areas. Little or no expression of T antigen was detected in adult animals before visible tumor formation. In contrast, βh1/T transgenic mice developed only choroid plexus tumors. Transient transfection assays in prostate and adrenocortical tumor-derived cell lines showed that the Gγ- globin promoter is 7- to 10-fold more active than the βh1-globin promoter. Activity of 5' Gγ-globin promoter-deletion DNA plasmids was analyzed by transient transfection in a variety of human prostate cancer cell lines. The Gγ-globin promoter region between -140 and -201 also showed high activity in the androgen-independent human prostate cancer cell lines DU-145 and PPC-1, but low activity in the androgen-responsive human prostate cell line LNCaP. We conclude that tumor formation in the Gγ/T transgenic lines apparently results from cryptic positive DNA cis elements active in prostate and adrenocortical cells. Because Gγ-globin promoter activity is highest in embryonic tissue, tumors in adult transgenic mice may result from expression of T antigen in embryonic prostate, adrenal glands, and brown adipose tissue.
|Original language||English (US)|
|Number of pages||11|
|State||Published - Feb 1 1996|
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Molecular Biology
- Cell Biology