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. 1993 Apr 1;90(7):2910–2914. doi: 10.1073/pnas.90.7.2910

Rhabdomyosarcoma arising in transgenic mice harboring the beta-globin locus control region fused with simian virus 40 large T antigen gene.

T Teitz 1, J C Chang 1, M Kitamura 1, T S Yen 1, Y W Kan 1
PMCID: PMC46206  PMID: 7681991

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams J. M., Cory S. Transgenic models of tumor development. Science. 1991 Nov 22;254(5035):1161–1167. doi: 10.1126/science.1957168. [DOI] [PubMed] [Google Scholar]
  2. Antoniou M., Grosveld F. beta-globin dominant control region interacts differently with distal and proximal promoter elements. Genes Dev. 1990 Jun;4(6):1007–1013. doi: 10.1101/gad.4.6.1007. [DOI] [PubMed] [Google Scholar]
  3. Behringer R. R., Peschon J. J., Messing A., Gartside C. L., Hauschka S. D., Palmiter R. D., Brinster R. L. Heart and bone tumors in transgenic mice. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2648–2652. doi: 10.1073/pnas.85.8.2648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blom van Assendelft G., Hanscombe O., Grosveld F., Greaves D. R. The beta-globin dominant control region activates homologous and heterologous promoters in a tissue-specific manner. Cell. 1989 Mar 24;56(6):969–977. doi: 10.1016/0092-8674(89)90630-2. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Curtin P. T., Liu D. P., Liu W., Chang J. C., Kan Y. W. Human beta-globin gene expression in transgenic mice is enhanced by a distant DNase I hypersensitive site. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7082–7086. doi: 10.1073/pnas.86.18.7082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dyer K. R., Messing A. Metal-inducible pathology in the liver, pancreas, and kidney of transgenic mice expressing SV40 early region genes. Am J Pathol. 1989 Aug;135(2):401–410. [PMC free article] [PubMed] [Google Scholar]
  8. Enver T., Ebens A. J., Forrester W. C., Stamatoyannopoulos G. The human beta-globin locus activation region alters the developmental fate of a human fetal globin gene in transgenic mice. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7033–7037. doi: 10.1073/pnas.86.18.7033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Felsenfeld G. Chromatin as an essential part of the transcriptional mechanism. Nature. 1992 Jan 16;355(6357):219–224. doi: 10.1038/355219a0. [DOI] [PubMed] [Google Scholar]
  10. Forrester W. C., Novak U., Gelinas R., Groudine M. Molecular analysis of the human beta-globin locus activation region. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5439–5443. doi: 10.1073/pnas.86.14.5439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gluzman Y. SV40-transformed simian cells support the replication of early SV40 mutants. Cell. 1981 Jan;23(1):175–182. doi: 10.1016/0092-8674(81)90282-8. [DOI] [PubMed] [Google Scholar]
  12. Grosveld F., van Assendelft G. B., Greaves D. R., Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987 Dec 24;51(6):975–985. doi: 10.1016/0092-8674(87)90584-8. [DOI] [PubMed] [Google Scholar]
  13. Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985 May 9;315(6015):115–122. doi: 10.1038/315115a0. [DOI] [PubMed] [Google Scholar]
  14. Hanscombe O., Vidal M., Kaeda J., Luzzatto L., Greaves D. R., Grosveld F. High-level, erythroid-specific expression of the human alpha-globin gene in transgenic mice and the production of human hemoglobin in murine erythrocytes. Genes Dev. 1989 Oct;3(10):1572–1581. doi: 10.1101/gad.3.10.1572. [DOI] [PubMed] [Google Scholar]
  15. Ikuta T., Kan Y. W. In vivo protein-DNA interactions at the beta-globin gene locus. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10188–10192. doi: 10.1073/pnas.88.22.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jaenisch R., Mintz B. Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1250–1254. doi: 10.1073/pnas.71.4.1250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mahon K. A., Chepelinsky A. B., Khillan J. S., Overbeek P. A., Piatigorsky J., Westphal H. Oncogenesis of the lens in transgenic mice. Science. 1987 Mar 27;235(4796):1622–1628. doi: 10.1126/science.3029873. [DOI] [PubMed] [Google Scholar]
  18. McAllister R. M., Melnyk J., Finkelstein J. Z., Adams E. C., Jr, Gardner M. B. Cultivation in vitro of cells derived from a human rhabdomyosarcoma. Cancer. 1969 Sep;24(3):520–526. doi: 10.1002/1097-0142(196909)24:3<520::aid-cncr2820240313>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  19. McKnight S., Tjian R. Transcriptional selectivity of viral genes in mammalian cells. Cell. 1986 Sep 12;46(6):795–805. doi: 10.1016/0092-8674(86)90061-9. [DOI] [PubMed] [Google Scholar]
  20. Messing A., Chen H. Y., Palmiter R. D., Brinster R. L. Peripheral neuropathies, hepatocellular carcinomas and islet cell adenomas in transgenic mice. Nature. 1985 Aug 1;316(6027):461–463. doi: 10.1038/316461a0. [DOI] [PubMed] [Google Scholar]
  21. Moi P., Kan Y. W. Synergistic enhancement of globin gene expression by activator protein-1-like proteins. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9000–9004. doi: 10.1073/pnas.87.22.9000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Murphy D., Bishop A., Rindi G., Murphy M. N., Stamp G. W., Hanson J., Polak J. M., Hogan B. Mice transgenic for a vasopressin-SV40 hybrid oncogene develop tumors of the endocrine pancreas and the anterior pituitary. A possible model for human multiple endocrine neoplasia type 1. Am J Pathol. 1987 Dec;129(3):552–566. [PMC free article] [PubMed] [Google Scholar]
  23. Ney P. A., Sorrentino B. P., McDonagh K. T., Nienhuis A. W. Tandem AP-1-binding sites within the human beta-globin dominant control region function as an inducible enhancer in erythroid cells. Genes Dev. 1990 Jun;4(6):993–1006. doi: 10.1101/gad.4.6.993. [DOI] [PubMed] [Google Scholar]
  24. Orkin S. H. Globin gene regulation and switching: circa 1990. Cell. 1990 Nov 16;63(4):665–672. doi: 10.1016/0092-8674(90)90133-y. [DOI] [PubMed] [Google Scholar]
  25. Ornitz D. M., Hammer R. E., Messing A., Palmiter R. D., Brinster R. L. Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice. Science. 1987 Oct 9;238(4824):188–193. doi: 10.1126/science.2821617. [DOI] [PubMed] [Google Scholar]
  26. Palmiter R. D., Chen H. Y., Messing A., Brinster R. L. SV40 enhancer and large-T antigen are instrumental in development of choroid plexus tumours in transgenic mice. Nature. 1985 Aug 1;316(6027):457–460. doi: 10.1038/316457a0. [DOI] [PubMed] [Google Scholar]
  27. Philipsen S., Talbot D., Fraser P., Grosveld F. The beta-globin dominant control region: hypersensitive site 2. EMBO J. 1990 Jul;9(7):2159–2167. doi: 10.1002/j.1460-2075.1990.tb07385.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Razin S. V., Petrov P., Hancock R. Precise localization of the alpha-globin gene cluster within one of the 20- to 300-kilobase DNA fragments released by cleavage of chicken chromosomal DNA at topoisomerase II sites in vivo: evidence that the fragments are DNA loops or domains. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8515–8519. doi: 10.1073/pnas.88.19.8515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Reynolds R. K., Hoekzema G. S., Vogel J., Hinrichs S. H., Jay G. Multiple endocrine neoplasia induced by the promiscuous expression of a viral oncogene. Proc Natl Acad Sci U S A. 1988 May;85(9):3135–3139. doi: 10.1073/pnas.85.9.3135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ryan T. M., Behringer R. R., Martin N. C., Townes T. M., Palmiter R. D., Brinster R. L. A single erythroid-specific DNase I super-hypersensitive site activates high levels of human beta-globin gene expression in transgenic mice. Genes Dev. 1989 Mar;3(3):314–323. doi: 10.1101/gad.3.3.314. [DOI] [PubMed] [Google Scholar]
  31. Ryan T. M., Behringer R. R., Townes T. M., Palmiter R. D., Brinster R. L. High-level erythroid expression of human alpha-globin genes in transgenic mice. Proc Natl Acad Sci U S A. 1989 Jan;86(1):37–41. doi: 10.1073/pnas.86.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Su W., Jackson S., Tjian R., Echols H. DNA looping between sites for transcriptional activation: self-association of DNA-bound Sp1. Genes Dev. 1991 May;5(5):820–826. doi: 10.1101/gad.5.5.820. [DOI] [PubMed] [Google Scholar]
  33. Talbot D., Philipsen S., Fraser P., Grosveld F. Detailed analysis of the site 3 region of the human beta-globin dominant control region. EMBO J. 1990 Jul;9(7):2169–2177. doi: 10.1002/j.1460-2075.1990.tb07386.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tsai S. F., Martin D. I., Zon L. I., D'Andrea A. D., Wong G. G., Orkin S. H. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature. 1989 Jun 8;339(6224):446–451. doi: 10.1038/339446a0. [DOI] [PubMed] [Google Scholar]
  35. Tuan D. Y., Solomon W. B., London I. M., Lee D. P. An erythroid-specific, developmental-stage-independent enhancer far upstream of the human "beta-like globin" genes. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2554–2558. doi: 10.1073/pnas.86.8.2554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tuan D., Kong S., Hu K. Transcription of the hypersensitive site HS2 enhancer in erythroid cells. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11219–11223. doi: 10.1073/pnas.89.23.11219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tuan D., Solomon W., Li Q., London I. M. The "beta-like-globin" gene domain in human erythroid cells. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6384–6388. doi: 10.1073/pnas.82.19.6384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Walters M., Martin D. I. Functional erythroid promoters created by interaction of the transcription factor GATA-1 with CACCC and AP-1/NFE-2 elements. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10444–10448. doi: 10.1073/pnas.89.21.10444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Windle J. J., Albert D. M., O'Brien J. M., Marcus D. M., Disteche C. M., Bernards R., Mellon P. L. Retinoblastoma in transgenic mice. Nature. 1990 Feb 15;343(6259):665–669. doi: 10.1038/343665a0. [DOI] [PubMed] [Google Scholar]
  40. Woychik R. P., Stewart T. A., Davis L. G., D'Eustachio P., Leder P. An inherited limb deformity created by insertional mutagenesis in a transgenic mouse. Nature. 1985 Nov 7;318(6041):36–40. doi: 10.1038/318036a0. [DOI] [PubMed] [Google Scholar]
  41. Yamamoto M., Ko L. J., Leonard M. W., Beug H., Orkin S. H., Engel J. D. Activity and tissue-specific expression of the transcription factor NF-E1 multigene family. Genes Dev. 1990 Oct;4(10):1650–1662. doi: 10.1101/gad.4.10.1650. [DOI] [PubMed] [Google Scholar]

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