Rhabdomyosarcoma arising in transgenic mice harboring the beta-globin locus control region fused with simian virus 40 large T antigen gene.
The beta-globin locus control region (LCR) confers a high level of erythroid-specific and copy-number-dependent expression to human globin genes in transgenic mice. Simian virus 40 T (tumor) antigen (Tag) with its own natural enhancer causes choroid plexus tumors in mice. We investigated the effect of the LCR on Tag gene expression, reasoning that mice harboring a LCR-Tag fusion gene might develop hematopoietic malignancies. To test this hypothesis we introduced an enhancerless Tag gene downstream of a LCR cassette into the germ lines of mice. The phenotypes of the transgenic mice depended on the copy number of the transgene. While mice with 1-2 copies matured normally, those with 3-7 copies developed rhabdomyosarcomas in different anatomic sites at high frequency and showed hyperplasia of the pancreatic islet cells which progressed to pancreatic islet tumors. In addition, the mice bearing 7 copies of the transgene had hypoglycemia and were stunted in growth. Mice with more than 10 copies were markedly stunted in growth and died within 2-4 weeks. Tag expression was detected at high levels in the mouse tumors but not in any other tissues, including the hematopoietic cells.
Teitz
T
T
Howard Hughes Medical Institute, San Francisco, CA.
Chang
J C
JC
Kitamura
M
M
Yen
T S
TS
Kan
Y W
YW
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D001483:Base Sequence; D005260:Female; D005809:Genes, Regulator; D005914:Globins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology; D009838:Oligodeoxyribonucleotides; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D013539:Simian virus 40 / Q000235:genetics*
D000952:Antigens, Polyomavirus Transforming; D009838:Oligodeoxyribonucleotides; D012334:RNA, Neoplasm; D012313:RNA; D005914:Globins