Integrating nuclear receptor and signaling pathways involved in cell proliferation and differentiation.

摘要

Nuclear receptors (NRs) are hormone-controlled transcription factors that regulate proliferation, survival, and differentiation of their target cells. Ultimately the action of these receptors affects development, metabolism, and homeostasis of higher organisms. Initial research on NRs focused on the ability of these receptors to interact with DNA and to regulate gene expression. Recently, the focus has been expanded to understand how cells integrate the actions of NRs with other signal transduction pathways. A current limitation of these analyses is the lack of a suitable model system that enables the genetic dissection of the relevant signaling networks.; Cell proliferation is one of the cellular responses to hormones that depends on functional interactions of NRs with other signal transduction pathways, such as the Wnt-pathway. The first goal of my dissertation was to investigate the mechanisms that enable cells to coordinate their responses to glucocorticoids (GCs) and Wnt. By analyzing the transcriptional regulation of several Wnt- and GC-responsive genes involved in cell cycle regulation, found that the glucocorticoid receptor (GR) represses the expression of the cell cycle regulator cyclin D1 through interactions with beta-catenin, the main effector of Wnt-pathways. The results of these studies indicated that GC and Wnt-pathways are able to communicate directly through their effectors. Both GC and Wnt-pathways regulate the proliferation of bone cells. Hence the mechanisms identified in my work could be of interest for the development of GC therapies that have lower risks of osteoporosis.; Presently, zebrafish is the only vertebrate that can be used for forward genetics. The second goal of my dissertation was to explore whether zebrafish could serve as a model organism to analyze hormone actions using thyroid hormone (TH) as an example. Although, the general mechanisms of TH action appear to be similar in zebrafish and mammals, I identified that zebrafish has a seemingly unique mechanisms to regulate the expression and activity of TRs.; This dissertation contains previously published co-authored materials.