β-catenin regulates GnRH-induced FSHβ gene expression.
The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of β-catenin in LHβ induction by GnRH has been discovered. We examined the role of β-catenin in FSHβ gene expression in LβT2 gonadotrope cells. GnRH caused a sustained increase in nuclear β-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition. Small interfering RNA-mediated knockdown of β-catenin mRNA demonstrated that induction of FSHβ mRNA by GnRH depended on β-catenin and that regulation of FSHβ by β-catenin occurred independently of the JNK-c-jun pathway. β-Catenin depletion had no impact on FSHβ mRNA stability. In LβT2 cells transfected with FSHβ promoter luciferase fusion constructs, GnRH responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by β-catenin knockdown. However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by GnRH. Chromatin immunoprecipitation further corroborated the absence of direct interaction between β-catenin and the 1.8-kb FSHβ promoter. To elucidate the mechanism for the β-catenin effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing β-catenin knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study. Subsequent experiments confirmed that Brms1L mRNA expression was decreased by β-catenin knockdown as well as by JNK inhibition. Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSHβ expression. Thus, our findings indicate that the expression of Brms1L depends on β-catenin activity and contributes to FSHβ induction by GnRH.
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CHEMICAL GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
GnRH T-cell factor/lymphoid enhancer factor binding sites GnRH β-catenin FSHβ promoter β-catenin β-catenin breast cancer metastasis-suppressor 1-like Brms1L Brms1L GnRH β-catenin gonadotropin JNK Brms1L GnRH FSHβ Brms1L β-catenin gonadotropin FSHβ GnRH GnRH β-catenin GnRH β-catenin FSHβ GnRH β-catenin GnRH c-Jun N-terminal kinase JNK GnRH β-catenin FSHβ GnRH β-catenin FSHβ β-catenin JNK c-jun β-Catenin FSHβ GnRH FSHβ promoter GnRH β-catenin β-catenin GnRH FSHβ GnRH GnRH N GnRH GnRH