| Estrogen action in the pituitary is mediated by the estrogen receptor alpha (ERalpha), and estrogen sensitivity varies throughout the reproductive cycle. A pituitary specific ERalpha isoform, Truncated Estrogen Receptor Product (TERP) modulates ER activity biphasically. At low concentrations TERP stimulates ERalpha transcriptional activity, whereas high concentrations of TERP reduce ligand-dependent and independent ER-mediated transcription. This suggests that TERP could modulate the estrogen sensitivity in the pituitary before and after the surge of luteinizing hormone (LH).; The inhibitory effect of TERP on ERalpha transcriptional activity is mainly due to the TERP-ER heterodimer formation, which impairs ERalpha binding to DNA. On the other hand, the stimulatory effect of TERP is the result of its binding to repressor proteins such as Repressor of Estrogen receptor Activity (REA). REA mRNA is expressed in the mouse and rat pituitary and the REA protein interacts with TERP in GST pulldown experiments. TERP effectively competes with ERalpha in binding to REA, even at low levels of TERP, and a dimerization mutant, TERP L509R, stimulates ERalpha transcription and abolishes the suppression by REA.; Changes in REA availability may alter ERalpha responses to both ligand and intracellular signaling pathways. During the rat estrous cycle, the mRNA expression of REA remains constant whereas the TERP level changes dramatically. We propose that the interaction between REA and ERalpha in the pituitary is regulated by TERP. In the rodent pituitary, the ligand-independent activation of ERalpha by forskolin (FSK) acts predominantly through protein kinase A (PKA). FSK can modulate REA activity by preventing its localization to the nucleus. Whereas wild type REA localizes to the nucleus, the S91E mutant aggregates around the perinuclear membrane. In transient transfection experiments, the S91E mutant of REA also fails to suppress FSK or E2 stimulated ERalpha activity.; These studies demonstrated that ERalpha activity is enhanced through distinct mechanisms involving cellular availability of REA. The ligand-dependent activation of ERalpha is increased by TERP binding to and decreasing the availability of REA. Conversely, ERalpha activation by PKA is increased by limiting REA access to the nucleus, and possibly by altering the interaction of REA with other suppressive proteins. |
