Objective:The ovarian-specific promoter, OSP-1, which was cloned from the transcript of a rat retrovirus-like element specifically expressed in ovarian tissue, was tested for its ability to drive ovary-specific transcription in transgenic mice.
Methods:Transgenic mice were generated with the lacZ reporter gene (OSP-lacZ) or the early region of SV40 virus (OSP-TAg) placed under the control of the OSP-1 promoter. OSP-lacZ and OSP-TAg transgenic animals were examined, respectively, for the expression of lacZ (OSP-lacZ) or the development of tumors (OSP-TAg).
Results:The expression of lacZ in the resulting OSP-lacZ mice was restricted to the ovary as determined by X-gal staining of multiple organs. Immunohistochemical detection of β-galactosidase showed lacZ expression mainly in the granulosa cells and ovarian surface epithelial cells. OSP-TAg mice developed tumors in a variety of tissues, including unilateral granulosa cell tumors in two of three female founder mice. In the contralateral ovary of one mouse with a granulosa cell tumor, there wee alterations in the ovarian surface epithelial cells suggestive of preneoplasia.
Conclusions:Although the OSP-1 promoter was able to restrict reporter gene expression to the ovary in transgenic mice, the expression of TAg in the OSP-TAg mice resulted in ovarian tumors as well as tumors in numerous other organs. This indicated that although transcription from the OSP-1 promoter occurs predominantly in the ovary, this promoter is sufficiently leaky in cells in other tissues to permit their tumorigenic conversion by SV40 TAg.
1. Ong A, Maines-Bandiera SL, Roskelley CD, Auersperg N. An ovarian adenocarcinoma line derived from SV40/E-cadherintransfected normal human ovarian surface epithelium. Int J Cancer2000;85:430-437.
2.
2. Abdollahi A, Godwin AK, Miller PD, et al. Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells. Cancer Res1997;57:2029-2034.
3.
3. Roby KF, Taylor CC, Sweetwood JP, et al. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis2000;21:585-591.
4.
4. Orsulic S, Li Y, Soslow RA, Vitale-Cross LA, Gutkind JS, Varmus HE. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell2002;1:53-62.
5.
5. Kananen K, Markkula M, Rainio E, Su JG, Hsueh AJ, Huhtaniemi IT. Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/simin virus T-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines. Mol Endocrinol1995;9:616-627.
6.
6. Dutertre M, Gouedard L, Xavier F, et al. Ovarian granulosa cell tumors express a functional membrane receptor for anti-Mullerian hormone in transgenic mice. Endocrinology2001;142:4040-4046.
7.
7. Godwin AK, Miller PD, Getts LA, et al. Retroviral-like sequences specifically expressed in the rat ovary detect genetic differences between normal and transformed rat ovarian surface epithelial cells. Endocrinology1995;136:4640-4649.
8.
8. Selvakumaran M, Bao R, Crijns AP, Connolly DC, Weinstein JK, Hamilton TC. Ovarian epithelial cell lineage-specific gene expression using the promoter of a retrovirus-like element. Cancer Res2001;61:1291-1295.
9.
9. Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature1985;315:115-122.
10.
10. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: A laboratory manual. 2nd ed.Cold Spring Harbor, Maine: Cold Spring Harbor Laboratory Press, 1989.
11.
11. Cohen-Tannoudji M, Vandormael-Pournin S, Drezen J, Mercier P, Babinet C, Morello D. lacZ sequences prevent regulated expression of housekeeping genes. Mech Dev2000;90:29-39.
12.
12. Saenz-Robles MT, Sullivan CS, Pipas JM. Transforming functions of simian virus 40. Oncogene2001;20:7899-7907.
