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GATA-4 Regulates Bcl-2 Expression in Ovarian Granulosa Cell Tumors

Children’s Hospital and Institute of Biomedicine (A.K., M.R., M.T., M.H.) and Program for Women’s Health (A.K., M.R., M.T., R.B., M.H., M.A.), Biomedicum Helsinki, and Departments of Obstetrics and Gynecology (L.U.-K., A.L., R.B., M.A.) and Pathology (R.B.), University of Helsinki, 00014 Helsinki, Finland; Cardiac Growth and Differentiation Unit (M.N.), Clinical Research Institute of Montreal, Montreal, Quebec, Canada H3A 2B4; Department of Physiology (N.R.), University of Turku, 20014 Turku, Finland; Department of Reproductive Biology (I.H.), Imperial College London, London W12 0NN, United Kingdom; and Department of Pediatrics (M.H.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Markku Heikinheimo, M.D., Ph.D., Children’s Hospital, University of Helsinki, P.O. Box 22 (Stenbäckinkatu 11), 00014 Helsinki, Finland. E-mail: markku.heikinheimo{at}helsinki.fi.

Excessive cell proliferation and decreased apoptosis have been implicated in the pathogenesis of ovarian granulosa cell tumors (GCTs). We hypothesized that transcription factor GATA-4 controls expression of the antiapoptotic factor Bcl-2 and the cell cycle regulator cyclin D2 in normal and neoplastic granulosa cells. To test this hypothesis, a tissue microarray based on 80 GCTs was subjected to immunohistochemistry for GATA-4, Bcl-2, and cyclin D2, and the data were correlated to clinical and histopathological parameters. In addition, quantitative RT-PCR for GATA-4, Bcl-2, and cyclin D2 was performed on 21 human GCTs. A mouse GCT model was used to complement these studies. The role of GATA-4 in the regulation of Bcl2 and ccdn2 (coding for cyclin D2) was studied by transactivation assays, and by disrupting GATA-4 function with dominant negative approaches in mouse and human GCT cell lines. We found that GATA-4 expression correlated with Bcl-2 and cyclin D2 expression in human and murine GCTs. Moreover, GATA-4 enhanced Bcl-2 and cyclin D2 promoter activity in murine GCT cells. Whereas GATA-4 overexpression up-regulated and dominant negative GATA-4 suppressed Bcl-2 expression in human GCT cells, the effects on cyclin D2 were negligible. Our results reveal a previously unknown relationship between GATA-4 and Bcl-2 in mammalian granulosa cells and GCTs, and suggest that GATA-4 influences granulosa cell fate by transactivating Bcl-2.