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Regulation of mRNA by GnRH through the RNA-binding protein HuR.


The hypothalamic-pituitary-gonadal axis is a principal regulator of reproduction in mammals. GnRH, a pivotal component of this axis, regulates the synthesis and secretion of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the gonadotropes of the anterior pituitary. LH synthesis is regulated at two different levels, the transcriptional and the post-transcriptional/ translational level. Previous studies have shown that GnRH activates cap-dependent translation promoting translation of mRNAs. Translational regulation by GnRH is specific to some mRNAs and occurs independently of transcription. Evaluation of polyribosome profiles in GnRH-stimulated L[Beta]T2 gonadotrope cells showed LH[Beta] mRNA redistributes to the transiently paused pool of mRNA as part of the unfolded protein response (UPR). In contrast, the mRNA encoding Dusp1, a protein phosphatase critical in resolving activation of MAP kinases, redistributes to actively translating polyribosomes. Dusp-1 mRNA is regulated and stabilized by various mRNA-binding proteins such as HuR (Human Antigen R, or ELAV1 in mice at its 3' UTR) and NF 90. Dusp1 mRNA encodes a binding site for the ARE (AU Rich Element)-binding protein HuR. Under chemical insult, HuR interaction stabilizes Dusp1 mRNA and promotes its translation. This drew our attention to whether GnRH regulates the translation of Dusp1 mRNA via HuR. Immunofluorescence experiments determined that treatment with GnRH promotes shuttling of HuR, to the nucleus and by blocking various signaling pathways it was determined that this translocation is MAP kinase dependent.

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