GATA-4 is a granulosa cell factor employed in inhibin-α activation by the TGF-β pathway
| Autor: | Mikko Anttonen, David B. Wilson, Antti Kyrönlahti, Olli Ritvos, Markku Heikinheimo, Malgorzata Bielinska, Helka Parviainen |
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| Rok vydání: | 2006 |
| Předmět: |
Transcriptional Activation
endocrine system medicine.medical_specialty Transcription Genetic Granulosa cell SMAD Biology Cell Line Paracrine signalling Endocrinology Transforming Growth Factor beta Internal medicine Chlorocebus aethiops TGF beta signaling pathway medicine Animals Humans Inhibins Smad3 Protein Promoter Regions Genetic Molecular Biology Transcription factor Regulation of gene expression Granulosa Cells Transforming growth factor beta GATA4 Transcription Factor Cell biology Gene Expression Regulation Cell culture COS Cells biology.protein Female hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Journal of Molecular Endocrinology. 36:557-568 |
| ISSN: | 1479-6813 0952-5041 |
| Popis: | Part of heterodimeric inhibin, inhibin-α is crucial for mammalian ovarian function. Regulation of inhibin-α expression in granulosa cells is both endocrine, primarily by follicle-stimulating hormone (FSH), and paracrine, primarily by members of the transforming growth factor β (TGF-β) superfamily. Smad proteins transmit TGF-β signals to the nucleus, but the cooperating transcription factors involved in inhibin-α promoter activation remain unknown. Transcription factor GATA-4 regulates inhibin-α in gonadal cells, and the FSH cascade activates GATA-4. We hypothesized that the TGF-β signalling cascade and GATA-4 also cooperate to regulate inhibin-α expression. In KK-1 granulosa tumour cells, which resemble normal granulosa cells and express inhibin-α, we found that TGF-β 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-α promoter attenuated TGF-β-induced gene activation. In GATA-4-deficient COS-7 cells, TGF-β enhanced the expression of the inhibin-α promoter only in the presence of exogenous GATA-4. Smad3, but not Smad2, cooperated with GATA-4 in the transcriptional activation of the inhibin-α 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-β signalling to activate inhibin-α in granulosa cells. |
| Databáze: | OpenAIRE |
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