Nuclear receptors, or ligand-regulated transcription factors, play critical roles in both physiology and disease by activating or repressing the transcription of target genes. In fact, nuclear receptors are the targets of many current therapeutics: ranging from treatment of breast cancer, to inflammation, to type 2 diabetes. Ligands control nuclear receptor conformation, and thus the recruitment of coactivator or corepressor proteins in order to coordinate the appropriate transcriptional machinery for a given physiological response. The two major corepressor proteins, SMRT and NCoR, originate from distinct genetic loci and are both subject to alternative mRNA splicing, which results in a host of unique corepressor splice variants. These different corepressor isoforms possess diverse structures, discreet interactions with transcription factors and unique physiological functions. Current therapeutics that target nuclear receptors commonly induce adverse side effects, or lose efficacy over time due to resistance. We propose that corepressor diversity may be a means for more specifically targeting nuclear receptor signaling to mediate disease. To investigate this hypothesis further, my dissertation will discuss our attempts to understand the regulation of corepressor alternative mRNA splicing, novel corepressor-nuclear receptor interaction domains and the distinctive biological functions of SMRT and NCoR splice variants. My efforts revealed that the alternative splicing of corepressors is hormonally and nutritionally controlled in both in vitro and in vivo models relevant to energy metabolism, indicating its importance in regulating glucose and lipid homeostasis. In addition, we report that selective modulators of estrogen receptor (&Egr;R) recruit corepressors via a novel mechanism, suggesting the need to broaden the classical model of ER-corepressor interaction, as well as potential new avenues to therapeutically target ER. We also found that different SMRT and NCoR splice variants seem to play distinct roles in activation and suppression of the inflammatory response, alluding that corepressor isoforms themselves may be a worthy therapeutic space.
|Commitee:||Denison, Michael S., Hammock, Bruce D.|
|School:||University of California, Davis|
|Department:||Pharmacology and Toxicology|
|School Location:||United States -- California|
|Source:||DAI-B 77/02(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Endocrinology, Pharmacology|
|Keywords:||Alternative mRNA splicing, Corepressors, Energy metabolism, Nuclear receptors, Transcriptional regulation|
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