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Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.

ABSTRACT: Mechanisms and signals that regulate transcriptional coactivators are still largely unknown. Here we provide genetic evidence for a repressor that interacts with and regulates the nuclear receptor coactivator PGC-1. Association with the repressor requires a PGC-1 protein interface that is similar to the one used by nuclear receptors. Removal of the repressor enhances PGC-1 coactivation of steroid hormone responses. We also provide evidence that interaction of the repressor with PGC-1 is regulated by mitogen-activated protein kinase (MAPK) signaling. Activation of the MAPK p38 enhances the activity of wild-type PGC-1 but not of a PGC-1 variant that no longer interacts with the repressor. Finally, p38 activation enhances steroid hormone response in a PGC-1-dependent manner. Our data suggest a model where the repressor and nuclear receptors compete for recruiting PGC-1 to an inactive and active state, respectively. Extracellular signals such as nuclear receptor ligands or activators of the MAPK p38 can shift the equilibrium between the two states.

SUBMITTER: Knutti D

PROVIDER: S-EPMC55518 | biostudies-literature | 2001 Aug

REPOSITORIES: biostudies-literature

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Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.

Knutti D D Kressler D D Kralli A A

Proceedings of the National Academy of Sciences of the United States of America 20010731 17

Mechanisms and signals that regulate transcriptional coactivators are still largely unknown. Here we provide genetic evidence for a repressor that interacts with and regulates the nuclear receptor coactivator PGC-1. Association with the repressor requires a PGC-1 protein interface that is similar to the one used by nuclear receptors. Removal of the repressor enhances PGC-1 coactivation of steroid hormone responses. We also provide evidence that interaction of the repressor with PGC-1 is regulate ...[more]

PMID: 11481440

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Project description:The β3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). The β3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by β3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1α regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1α regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.

Dataset Information

Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.

Publications

Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.

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