GATA-4 regulates Bcl-2 expression in ovarian granulosa cell tumors.
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.
Kyrönlahti
Antti
A
Children's Hospital and Institute of Biomedicine, University of Helsinki, 00014 Helsinki, Finland.
Rämö
Maarit
M
Tamminen
Maija
M
Unkila-Kallio
Leila
L
Butzow
Ralf
R
Leminen
Arto
A
Nemer
Mona
M
Rahman
Nafis
N
Huhtaniemi
Ilpo
I
Heikinheimo
Markku
M
Anttonen
Mikko
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D005260:Female; D050991:GATA4 Transcription Factor / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006106:Granulosa Cell Tumor / Q000235:genetics*; D006801:Humans; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human