Dissertation
The role of [beta]-catenin in the gonadotrope transcriptional network: interactions with SF1 and TCF
Washington State University
Doctor of Philosophy (PhD), Washington State University
12/2009
DOI:
https://doi.org/10.7273/000005971
Abstract
Gonadotropin-releasing hormone (GnRH) is necessary for the regulation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) synthesized and secreted from gonadotrope cells of the anterior pituitary. GnRH signals to regulate genes through a transcriptional hierarchy, and herein we show that the co-factor [beta]-catenin is a required component of this network. GnRH stimulates [beta]-catenin accumulation and is required for expression of several gonadotrope specific genes through interactions with steroidogenic factor 1 (SF1) and T-cell factor (TCF). Regulation of the four gonadotrope specific genes, Lhb, Fshb, Cga and Gnrhr requires SF1 in addition to several immediate early genes that confer hormonal responsiveness including Jun and Atf3. The work presented here demonstrates that SF1 and [beta]-catenin interactions are necessary for maximal regulation of Lhb subunit gene downstream of GnRH. This provides one input for [beta]-catenin in the gonadotrope transcriptional network and suggests that the co-factor may be important in regulation of the other gonadotrope specific genes. Beta-catenin was originally identified as a downstream mediator of WNT signaling through interactions with TCF proteins. A requirement for TCF in regulation of Jun/JUN downstream of GnRH provides a second input for [beta]-catenin in the transcriptional network. TCF and [beta]-catenin interactions are necessary for Jun mRNA accumulation, as well as transcriptional activity of a truncated CGA promoter reporter. These observations suggest that similar signaling pathways may mediate TCF-dependent transcription downstream of GnRH. We have found that similar signaling pathways regulate increased message of both Jun and Atf3. Furthermore, we found that the signaling pathway that mediates these events downstream of GnRH requires calcium mobilization and calcineurin activity. Increased cellular calcium and calcineurin activity is necessary for GnRH regulation of an NFAT responsive promoter, providing another possible site of action for [beta]-catenin through direct or indirect interactions. These studies demonstrate that [beta]-catenin is a key player in regulation of several gonadotrope genes, and interactions with SF1 and TCF are necessary for gonadotrope function.
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Details
- Title
- The role of [beta]-catenin in the gonadotrope transcriptional network
- Creators
- April Kay Binder
- Contributors
- John H. Nilson (Chair)Kwanhee Kim (Committee Member) - Washington State University, School of Molecular BiosciencesJohn Jason Wyrick (Committee Member) - Washington State University, School of Molecular BiosciencesJoseph W Harding (Committee Member) - Washington State University, Department of Integrative Physiology and Neuroscience
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 156
- Identifiers
- 99901055135901842
- Language
- English
- Resource Type
- Dissertation