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¹ Program for Developmental and Reproductive Biology, Biomedicum Helsinki,
² Children’s Hospital and Haartman Institute, University of Helsinki, 00014 Helsinki, Finland
³ Departments of Pediatrics and
⁴ Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, Missouri 63110, USA
⁵ Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland

(Requests for offprints should be addressed to M Heikinheimo at first address; Email: markku.heikinheimo{at}helsinki.fi)

^* (M Anttonen and H Parviainen contributed equally to this work)

Part of heterodimeric inhibin, inhibin- is crucial for mammalian ovarian function. Regulation of inhibin- expression in granulosa cells is both endocrine, primarily by follicle-stimulating hormone (FSH), and paracrine, primarily by members of the transforming growth factor ß (TGF-ß) superfamily. Smad proteins transmit TGF-ß signals to the nucleus, but the cooperating transcription factors involved in inhibin- promoter activation remain unknown. Transcription factor GATA-4 regulates inhibin- in gonadal cells, and the FSH cascade activates GATA-4. We hypothesized that the TGF-ß signalling cascade and GATA-4 also cooperate to regulate inhibin- expression. In KK-1 granulosa tumour cells, which resemble normal granulosa cells and express inhibin-, we found that TGF-ß upregulated GATA-4 expression. Transient transfection experiments in KK-1 cells demonstrated that dominant negative GATA-4 variants or mutations of GATA-binding sites in the inhibin- promoter attenuated TGF-ß-induced gene activation. In GATA-4-deficient COS-7 cells, TGF-ß enhanced the expression of the inhibin- promoter only in the presence of exogenous GATA-4. Smad3, but not Smad2, cooperated with GATA-4 in the transcriptional activation of the inhibin- promoter, and immunoprecipitation experiments in KK-1 cells revealed a physical Smad3:GATA-4 interaction. Our data suggest that GATA-4, interacting with Smad3, is a cofactor for TGF-ß signalling to activate inhibin- in granulosa cells.

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