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Transforming Growth Factor ß-Activated Kinase 1 Is a Key Mediator of Ovine Follicle-Stimulating Hormone ß-Subunit Expression

Department of Molecular and Structural Biochemistry (N.S., A.J.G., W.L.M.), North Carolina State University, Raleigh, North Carolina 27695-7622; and Department of Toxicology (J.N.-T.), North Carolina State University, Raleigh, North Carolina 27695-7633

Address all correspondence and requests for reprints to: William L. Miller, Department of Molecular and Structural Biochemistry, Box 7622, North Carolina State University, Raleigh, North Carolina 27695-7622. E-mail: wlmiller{at}ncsu.edu.

FSH, a key regulator of gonadal function, contains a ß-subunit (FSHß) that is transcriptionally induced by activin, a member of the TGFß-superfamily. This study used 4.7 kb of the ovine FSHß-promoter linked to luciferase (oFSHßLuc) plus a well-characterized activin-responsive construct, p3TPLuc, to investigate the hypothesis that Smad3, TGFß-activated kinase 1 (TAK1), or both cause activin-mediated induction of FSH. Overexpression of either Smad3 or TAK1 induced oFSHßLuc in gonadotrope-derived LßT2 cells as much as activin itself. Induction of p3TPLuc by activin is known to require Smad3 activation in many cell types, and this was true in LßT2 cells, where 10-fold induction by activin (2–8 h after activin treatment) was blocked more than 90% by two dominant negative (DN) inhibitors of Smad3 [DN-Smad3 (3SA) and DN-Smad3 (D407E)]. By contrast, 6.5-fold induction of oFSHßLuc by activin (10–24 h after activin treatment) was not blocked by either DN-Smad inhibitor, suggesting that activation of Smad3 did not trigger induction of oFSHßLuc. By contrast, inhibition of TAK1 by a DN-TAK1 construct led to a 50% decrease in activin-mediated induction of oFSHßLuc, and a specific inhibitor of TAK1 (5Z-7-Oxozeanol) blocked induction by 100%, indicating that TAK1 is necessary for activin induction of oFSHßLuc. Finally, inhibiting p38-MAPK (often activated by TAK1) blocked induction of oFSHßLuc by 60%. In conclusion, the data presented here indicate that activation of TAK1 (and probably p38-MAPK), but not Smad3, is necessary for triggering induction of oFSHß by activin.

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