Eukaryotic gene regulation by members of the nuclear receptor superfamily is crucial for a vast array of cellular and physiological processes including development, differentiation, proliferation and homeostasis. Regulation of the transcriptional activity of nuclear receptors occurs through the exchange of corepressor and coactivator complexes in a ligand-dependent manner. However, this may not be the case for orphan nuclear receptors, including RORalpha. Instead, RORalpha orphan nuclear receptor activity is modulated by Ca 2+/calmodulin-dependent protein kinase IV (CAMKIV), through a yet undetermined mechanism, and RORalpha itself regulates the expression of genes involved in the calcium signaling pathway. In this study, we report that RORalpha transcriptional activity is modulated by CaMKIV through direct phosphorylation of CIR, a novel nuclear receptor corepressor, thereby influencing its interactions with RORalpha. CIR exhibits ligand-oblivious and nuclear receptor AF-2 specific functional properties, similar to those of previously characterized RORalpha corepressor Hr. In contrast, the corepressors CIR and Hr display differential mechanisms of repression, comprising of HDAC-dependent and independent pathways, respectively. Furthermore, the calcium-dependent regulation of RORalpha transcriptional activity occuring through modulation of CIR does not extend to Hr, illustrating corepressor specificity. Thus, the molecular mechanisms governing active repression of RORalpha transcriptional activity involve distinct repression and signal transduction pathways, representing a dual mode of nuclear receptor regulation.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.81440 |
| Date | January 2004 |
| Creators | Singh, Jaspal, 1978- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002166509, proquestno: AAIMR06455, Theses scanned by UMI/ProQuest. |
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