GATA-4 regulates Bcl-2 expression in ovarian granulosa cell tumors

Title: GATA-4 regulates Bcl-2 expression in ovarian granulosa cell tumors
Authors: Anttonen, Mikko
Heikinheimo, Markku
Huhtaniemi, Ilpo
Leminen, Arto
Butzow, Ralf
Unkila-Kallio, Leila
Tamminen, Maija
Rahman, Nafis
Nemer, Mona
Rämö, Maarit
Kyrönlahti, Antti
Date: 2008
Abstract: 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.
DOI: 10.1210/en.2008-0148
CollectionCabinet VR, Recherche - Publications // Office VP, Research - Publications