Synergistic induction of follicle-stimulating hormone beta-subunit gene expression by gonadal steroid hormone receptors and Smad proteins.
LH and FSH play crucial roles in mammalian reproduction by mediating steroidogenesis and gametogenesis. Gonadal steroid hormones influence gonadotropin production via feedback to the hypothalamus and pituitary. We previously demonstrated that progesterone and testosterone can stimulate expression of the FSH beta-subunit gene in immortalized gonadotrope-derived LbetaT2 cells. Herein, we investigate how these gonadal steroids modulate activin signaling in the gonadotrope. Cotreatment of LbetaT2 cells or mouse primary pituitary cells with steroids and activin results in a synergistic induction of FSHbeta gene expression. This synergy decreases when DNA-binding mutations are introduced into the steroid receptors or when mutations that reduce steroid hormone responsiveness are introduced into the FSHbeta promoter, indicating that synergy requires direct DNA binding of the steroid receptors. Furthermore, classical activin signaling via Smad proteins is necessary for this synergy. In addition, these steroid receptors physically interact with Smads and are sufficient for the synergism to occur on the FSHbeta promoter. Disruption of Smad binding to the promoter with a Smad protein lacking the DNA-binding domain or an FSHbeta promoter containing mutated activin-response elements prevents the synergistic enhancement of FSHbeta transcription. Collectively, our data demonstrate that the molecular mechanism for gonadal steroid hormone action on the FSHbeta promoter involves cross-talk between the steroid and activin signaling pathways. They also reveal that this synergism requires binding of both the steroid receptors and Smad proteins to their cognate DNA-binding elements and likely involves a direct protein-protein interaction between the two types of transcription factors.
Thackray
Varykina G
VG
Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Mellon
Pamela L
PL
D028341:Activins / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004357:Drug Synergism; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D052681:Gonadotrophs / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology
D037201:Follicle Stimulating Hormone, beta Subunit; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D051785:Smad Proteins; D028341:Activins; D013739:Testosterone; D011374:Progesterone