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The transcriptional coactivator PGC-1[alpha] as a modulator of ERR[alpha] and GR signaling : function in mitochondrial biogenesis

Schreiber, Sylvia Nicole. The transcriptional coactivator PGC-1[alpha] as a modulator of ERR[alpha] and GR signaling : function in mitochondrial biogenesis. 2004, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_6931

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Abstract

The nuclear receptor family represents a large class of transcription factors that regulate metabolism, differentiation and development. Most of the nuclear receptor family members are orphan receptors, so called because no ligands were known when they were identified. Although for some receptors ligands have been identified by now, many receptors, such as the estrogen related receptor α (ERRα), still remain orphan. The activity of all nuclear receptors requires the recruitment of coregulators, which are able to enhance or repress their activity. Our work has focused on PGC-1α, which responds to physiological signals, such as cold, fasting and exercise, and was characterized as an important factor in the regulation of energy homeostasis and metabolic pathways. In my thesis work, we demonstrate that PGC-1α regulates the expression and activity of the orphan nuclear receptor ERRα. Our findings suggest that PGC-1α may act as a protein ligand, substituting for the lack of small lipohilic ligands for this receptor. The expression of PGC-1α and ERRα is parallel in tissues with high energy demand, and induced in vivo when animals are exposed to cold. Furthermore, our studies demonstrate that ERRα is important for PGC-1α signaling, since diminished ERRα levels significantly reduce the induction of mitochondrial biogenesis by PGC-1α. Binding sites for ERRα are observed in many genes encoding for mitochondrial proteins, and in vitro studies suggest that ERRα activates the transcription of at least a subset of the genes by binding to their promoters. Furthermore, ERRα fused to the potent VP16 activation domain is sufficient to induce mitochondrial biogenesis. We suggest that PGC-1α and ERRα regulate the transcription of genes encoding mitochondrial proteins in response to metabolic requirements.
Previous studies from our lab identified PGC-1α as a potent regulator of glucocorticoid receptor (GR) function in vitro. In support of our studies, other groups have shown that PGC-1α coactivates GR on the PEPCK promoter, the key enzyme of gluconeogenesis. Further data has shown that glucocorticoids and glucagon regulate the expression of PGC-1α. This led us to investigate the role of PGC-1α in GR signalling in SAOS2 cells. Our preliminary data suggest that glucocorticoids strongly influence PGC-1α signaling, enhancing some PGC-1α pathways and suppressing others. Finally, our data provide support to the hypothesis that PGC-1α is not a general enhancer of glucocorticoid responses, but rather provides specificity to GR signalling. PGC-1α expression leads to the activation of a distinct set of genes by GR. Future studies should provide more insight into this relationship.
Advisors:Hall, Michael N.
Committee Members:Kralli, N. and Meyer, Urs Albert
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:6931
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:203
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 14:57

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