GATA-4 is a granulosa cell factor employed in inhibin-α activation by the TGF-β pathway

Abstract

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 (TGF-) superfamily. Smad proteins transmit TGF-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 TGFsignalling 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-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--induced gene activation. In GATA-4-deficient COS-7 cells, TGF-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-signalling to activate inhibin-in granulosa cells.

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

“…We focused on TGF-b as GATA4 induced p15Ink4b, known to be regulated by TGF-b, including in astrocytes (Hannon and Beach, 1994;Quelle et al, 1995) (Rich et al, 1999). We found TGF-b stimulation induced GATA4 expression in astrocytes, a result which was also supported by studies in regulation of gastrointestinal differentiation genes (Afouda et al, 2005;Anttonen et al, 2006;Belaguli et al, 2007). Furthermore, our results showed that GATA4 knockdown inhibited TGF-b and p15Ink4b-mediated growth suppression in the astrocytes.…”

Calcineurin and CRTC2 mediate FSH and TGF 1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells

“…Also, TGFb1 increased the expression of transcription factor GATA4 in a granulosa tumor cell line KK1 (Anttonen et al 2006), and GATA4 has recently been reported to bind and stimulate FSH receptor promoter activity in mouse granulosa cells (Bennett et al 2012).…”

Adrenocortical tumorigenesis, luteinizing hormone receptor and transcription factors GATA-4 and GATA-6

“…Of interest, GATA-4 has recently been shown to cooperate with Smad3 to mediate TGFβ signalling in the regulation of inhibin α. (Anttonen et al 2006). Thus, TGFβ, Smad3…”