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GATA-1 and GATA-4 Transactivate Inhibin/Activin ß-B-Subunit Gene Transcription in Testicular Cells

Population Council (Z.-M.F., A.Z.W., C.-L.C.C.) and The Rockefeller University (C.-L.C.C.) New York, New York 10021

We have recently demonstrated that a testicular GATA-binding protein, GATA-1, up-regulates the transcription of inhibin -subunit gene through interaction with GATA motifs in the promoter region in MA-10, a mouse Leydig tumor cell line. In this study, we showed that both GATA-1 and GATA-4 also transactivated the transcription from the promoter for the 4.8-kb inhibin/activin ß-B-subunit gene transcripts, ß-B(4.8)-subunit promoter, in two testicular cell lines, MA-10 and MSC-1, which is a mouse Sertoli cell line. The abilities of GATA-1 and GATA-4 interacting with GATA and/or GATA-like sequences to transactivate the ß-B(4.8)-subunit promoter were next examined by mutation analysis. Mutations of GATA or GATA-like sequences caused no apparent effect or only a small decrease in the basal transcriptional activity of this promoter. However, mutation of the GATA motif at -65 markedly decreased 60–70% of the effect of GATA-1 on the transactivation of ß-B(4.8)-subunit promoter in both MA-10 and MSC-1 cells. In addition, mutation of the GATA motif in MSC-1 cells also reduced 40–50% of the effect of GATA-4 to transactivate this promoter. Interestingly, mutation of GATT at -42 caused a 70–90% increase in the transactivation of ß-B(4.8)-subunit promoter by GATA-1 or GATA-4. No significant change in the promoter activity was observed when GATT at -177 or GATC at -201 was mutated. Electrophoretic mobility shift assay confirmed the above observations that these GATA-binding proteins interacted with the GATA motif at -65 and GATT at -42, but not with GATC at -201 or GATT at -177. Serial deletion from the 5'-end of the basal promoter, from -226 to -90, markedly decreased the basal transcription, but increased the effect of GATA-1 on transactivation of the ß-B(4.8)-subunit promoter. In summary, our observations suggest that the two GATA-binding proteins transactivate the ß-B(4.8)-subunit promoter in testicular cells via complicated mechanisms. Both GATA-1 and GATA-4 factors act through the GATA motif at -65 and GATT at -42 to positively and negatively regulate the transcription from this promoter, respectively. Furthermore, GATA-1 may also interact directly or indirectly with DNA sequences at -180 to -90 to regulate the ß-B(4.8)-subunit promoter.

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