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Gonadotropin-Releasing Hormone-Mediated Phosphorylation of Estrogen Receptor- Contributes to fosB Expression in Mouse Gonadotrophs

Department of Obstetrics and Gynecology (J.C., B.-S.A., G.L.H., P.C.K.L.), Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5; and Shanghai Institute of Planned Parenthood Research (L.C.), Shanghai 20025, People’s Republic of China

Address all correspondence and requests for reprints to: Peter C. K. Leung, Ph.D., Department of Obstetrics and Gynecology, University of British Columbia, Room 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5. E-mail: peleung{at}interchange.ubc.ca.

Estrogen receptors (ERs) are activated by their ligands as well as signaling pathways that alter ER phosphorylation in response to peptide hormones and growth factors. In pituitary gonadotrophs, GnRHs act via the type I GnRH receptor (GnRHR). Both GnRH subtypes (GnRH-I and -II) activate an estrogen response element (ERE)-driven luciferase reporter gene in LβT2 mouse pituitary cells, and GnRH-I is most potent in this regard. Moreover, antide (a GnRH antagonist) and a GnRHR small interfering RNA (siRNA) abrogate this effect, whereas an ER antagonist (ICI 182,780) does not. The ER in LβT2 cells is phosphorylated at Ser¹¹⁸ in the nucleus and at Ser¹⁶⁷ in both nucleus and cytoplasm after GnRH treatments and coincided with increased ER binding to its coactivator, the p300/cAMP response element-binding protein-associated factor (PCAF). Moreover, siRNA-mediated knockdown of PCAF levels attenuated GnRH-induced ERE-luciferase transactivation in these cells. Most importantly, both GnRH subtypes robustly up-regulated expression of the immediate early response gene, fosB, whereas cotreatment with ER siRNA or PCAF siRNA attenuated this effect. This appears to occur at the transcriptional level because corecruitment of ER and PCAF to an ERE within the endogenous fosB promoter was increased by GnRH treatments, as shown by chromatin immunoprecipitation assays. These data demonstrate that GnRH-mediated phosphorylation of ER in mouse LβT2 pituitary cells results in its rapid association with PCAF and the transcriptional activation of fosB, and we demonstrate that this in turn likely activates other genes in pituitary cells including the FSH β-subunit gene.