Date of Award

Spring 5-17-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacological Sciences

First Advisor

Mitchell A. Lazar, M.D., Ph.D.

Abstract

Nuclear hormone receptors comprise a large family of ligand-sensitive transcription factors that can directly bind and regulate target genes to affect various physiological processes including development, differentiation, circadian rhythm and metabolism. Classically, activation of transcription by nuclear receptors (NRs) is due to a ligandinduced switch from corepressor- to coactivator-bound states. Highly analogous corepressors including NCoR and SMRT facilitate repression by NR via recruitment and activation of the histone deacetylase HDAC3. Liver X Receptor (LXR) is an NR that functions to regulate diverse physiological processes including cholesterol metabolism, lipid homeostasis, immunity and inflammation. Selective modulators of LXR to specifically target pathways for peripheral cholesterol efflux were developed and observed to function as partial agonists of LXR. We determined that the selective partial agonism of LXR by these ligands was indeed related to differential recruitment of the corepressor NCoR. Secondly, to understand the structural basis for physiological v repression of NR by NCoR we co-crystallized a small peptide comprising a region of the interaction domain of NCoR with the ligand-binding domain of Rev-erba. This revealed that the relative structural requirements for the previously reported antagonized PPARa- bound SMRT were distinct from that of the Rev-erba:NCoR complex. Altogether, these studies provide novel molecular insight into the function of NCoR in regulating transcription by nuclear hormone receptors.

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