Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element.
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The expression of estrogen-related receptor-alpha (ERRalpha) is stimulated by estrogen in selective tissues. Recently, a correlation between ERRalpha expression and the induction of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERRalpha regulation by diverse signals, the promoter of the human ERRalpha gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERRalpha gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells. Among the nuclear receptors tested, ERRgamma bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1alpha in HEC-1B cells strongly activated the reporter containing the MHRE, presumably via the endogenous nuclear receptor binding to the element. Reducing the endogenous level of ERRgamma by small interfering RNA, and increasing the ERRgamma level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1alpha. The activation function 2 domain of the ERRgamma and the L2 and L3 motifs of PGC-1alpha were essential to transactivate the MHRE. Additionally, PGC-1alpha increases the amount of endogenous ERRgamma bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERRalpha gene is a target for ERRgamma transactivation, which is enhanced by PGC-1alpha.
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ERRγ interacts with PGC-1 to regulate expression of ERRα.
“Although the physiological effects of the related gene ERR␥ remain unclear, it interacts with PGC-1 to regulate expression of ERR␣ (278), and polymorphisms at this locus were found to be associated with increased glucose area under the curve in a genetic analysis of Old Order Amish subjects (279).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [278]
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- Authors
- Liu, D., Zhang, Z., & Teng, C. T.
- Affiliations
- National Institutes of Health (US)
- Venue
- Journal of Molecular Endocrinology
- Publisher
- Bioscientifica
- Published
- 2005-04-01
- Volume
- 34
- Issue
- 2
- Pages
- 473-487
- ISSN
- 0952-5041 (ISSN-L)
- 1479-6813
- OpenAlex
- W2119377878
- Cited by
- 56
- References
- 66
- Citations by year
- 2024: 2 · 2023: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 2 · 2017: 3 · 2015: 4 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- estrogen-related receptor gamma, PGC-1α, estrogen-related receptor alpha, promoter regulation, transcriptional activation, estrogen regulation of gene expression, chromatin binding
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, ERRalpha Estrogen-Related Receptor, Animals, Base Sequence, Gene Expression Regulation, Heat-Shock Proteins, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Receptors, Estrogen, Recombinant Fusion Proteins, Transcription Factors, Genes, Reporter, Receptors, Cytoplasmic and Nuclear, Response Elements, RNA, Small Interfering, Cell Line, Tumor, Mice
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