Dissertation/Thesis Abstract

Nuclear receptor corepression, negative feedback and transcription-based oscillation: Evidence for a novel form of nuclear receptor regulation
by Heim, Kelly Christopher, Ph.D., Dartmouth College, 2009, 226; 3397936
Abstract (Summary)

Nuclear receptors (NRs) are ligand-regulated transcription factors that control gene expression through interaction with coregulator proteins. Receptor interacting protein 140 (RIP140) is a ligand-inducible, ligand-dependent NR corepressor with important roles in metabolic homeostasis. Previous work has demonstrated that RIP140 mediates negative feedback at the transcriptional level that limits retinoic acid receptor (RAR) activity. The RA induciblity of RIP140 and RAR repression by RIP140 predicts cyclic expression of cyclic RAR activity. This work sought to define the role of RIP140 in dynamic NR activity. The novel hypothesis to be tested was that RIP140 is a ligand-inducible NR corepressor that selectively and differentially regulates oscillatory NR signaling.

The data support that RIP140 limits activation of several NRs and is induced by multiple NR ligands. In contrast to classic NR coregulators that are not inducible with retinoic acid (RA) and are not limiting for RAR activity, RIP140 plays a non-redunant role in RA signaling. Furthermore, RIP140 exhibits selectivity in repressing RA target genes. In the constant presence of RA, it was found that RAR activity and RIP140 and RA target genes oscillate. These oscillations are influenced by RIP140 overexpression and depletion. The extended period of these oscillations are reminiscent of circadian rhythms, 24-hour cycles that coordinate metabolism with environmental and hormonal cues. The circadian system is directly regulated by retinoid related orphan receptors (RORs). We provide evidence of repression of ROR activity by RIP140 and potential regulation of RIP140 by RORs, supporting a novel role for RIP140 in clock regulation. Since RIP140 is a critical metabolic regulator, is hormone-inducible, and regulates numerous NRs with known roles in diurnal metabolic processes, it may constitute an important regulatory node in the integration of hormone signaling, energy flux, and the circadian machinery. This work identifies a novel temporal organization of RA signaling and supports a connection between the timing of NR signaling and the circadian clock. The extensive involvement of NRs and their coregulators in metabolic regulation and in disorders of energy balance and cancer suggest that RIP140 may affect diverse NR-dependent signaling events with far-reaching physiological and pharmacological ramifications.

Indexing (document details)
Advisor: Spinella, Michael J.
Commitee: Eastman, Alan R., Fiering, Steven N., Hwa, John
School: Dartmouth College
Department: Pharmacology and Toxicology
School Location: United States -- New Hampshire
Source: DAI-B 71/04, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Cellular biology, Pharmacology
Keywords: Circadian, Negative feedback, Nuclear receptor, Oscillator, RIP140, Retinoids
Publication Number: 3397936
ISBN: 9781109703535
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