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Title: Estrogen-related receptor {alpha} is essential for the expression of antioxidant protection genes and mitochondrial function

Abstract

Estrogen-related receptor {alpha} (ERR{alpha}) is an important mediator of mitochondrial biogenesis and function. To investigate the transcriptional network controlling these phenomena, we investigated mitochondrial gene expression in embryonic fibroblasts isolated from ERR{alpha} null mice. Peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) stimulated mitochondrial gene expression program in control cells, but not in the ERR{alpha} null cells. Interestingly, the induction of levels of mitochondrial oxidative stress protection genes in response to increased PGC-1{alpha} levels was dependent on ERR{alpha}. Furthermore, we found that the PGC-1{alpha}-mediated induction of estrogen-related receptor {gamma} and nuclear respiratory factor 2 (NRF-2), was dependent on the presence of ERR{alpha}. Basal levels of NRF-2 were decreased in the absence of ERR{alpha}. The absence of ERR{alpha} resulted in a decrease in citrate synthase enzyme activity in response to PGC-1{alpha} overexpression. Our results indicate an essential role for ERR{alpha} as a key regulator of oxidative metabolism.

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [3];  [3];  [2];  [2]
  1. Diabetes and Metabolism Disease Area, Novartis Institutes of BioMedical Research Institutes, 100 Technology Square, Cambridge, MA 02139 (United States). E-mail: shamina.rangwala@novartis.com
  2. Diabetes and Metabolism Disease Area, Novartis Institutes of BioMedical Research Institutes, 100 Technology Square, Cambridge, MA 02139 (United States)
  3. Genome and Proteome Sciences, Novartis Institutes of BioMedical Research Institutes, 500 Technology Square, Cambridge, MA 02139 (United States)
Publication Date:
OSTI Identifier:
20991357
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 357; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2007.03.126; PII: S0006-291X(07)00612-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; CARNITINE; CITRATES; ENZYME ACTIVITY; ESTROGENS; FIBROBLASTS; GENES; METABOLISM; MICE; MITOCHONDRIA; OXIDASES; OXIDATION; PHOSPHORYLATION; RECEPTORS; SUPEROXIDE DISMUTASE

Citation Formats

Rangwala, Shamina M., Li, Xiaoyan, Lindsley, Loren, Wang, Xiaomei, Shaughnessy, Stacey, Daniels, Thomas G., Szustakowski, Joseph, Nirmala, N.R., Wu, Zhidan, and Stevenson, Susan C.. Estrogen-related receptor {alpha} is essential for the expression of antioxidant protection genes and mitochondrial function. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.03.126.
Rangwala, Shamina M., Li, Xiaoyan, Lindsley, Loren, Wang, Xiaomei, Shaughnessy, Stacey, Daniels, Thomas G., Szustakowski, Joseph, Nirmala, N.R., Wu, Zhidan, & Stevenson, Susan C.. Estrogen-related receptor {alpha} is essential for the expression of antioxidant protection genes and mitochondrial function. United States. doi:10.1016/j.bbrc.2007.03.126.
Rangwala, Shamina M., Li, Xiaoyan, Lindsley, Loren, Wang, Xiaomei, Shaughnessy, Stacey, Daniels, Thomas G., Szustakowski, Joseph, Nirmala, N.R., Wu, Zhidan, and Stevenson, Susan C.. Fri . "Estrogen-related receptor {alpha} is essential for the expression of antioxidant protection genes and mitochondrial function". United States. doi:10.1016/j.bbrc.2007.03.126.
@article{osti_20991357,
title = {Estrogen-related receptor {alpha} is essential for the expression of antioxidant protection genes and mitochondrial function},
author = {Rangwala, Shamina M. and Li, Xiaoyan and Lindsley, Loren and Wang, Xiaomei and Shaughnessy, Stacey and Daniels, Thomas G. and Szustakowski, Joseph and Nirmala, N.R. and Wu, Zhidan and Stevenson, Susan C.},
abstractNote = {Estrogen-related receptor {alpha} (ERR{alpha}) is an important mediator of mitochondrial biogenesis and function. To investigate the transcriptional network controlling these phenomena, we investigated mitochondrial gene expression in embryonic fibroblasts isolated from ERR{alpha} null mice. Peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) stimulated mitochondrial gene expression program in control cells, but not in the ERR{alpha} null cells. Interestingly, the induction of levels of mitochondrial oxidative stress protection genes in response to increased PGC-1{alpha} levels was dependent on ERR{alpha}. Furthermore, we found that the PGC-1{alpha}-mediated induction of estrogen-related receptor {gamma} and nuclear respiratory factor 2 (NRF-2), was dependent on the presence of ERR{alpha}. Basal levels of NRF-2 were decreased in the absence of ERR{alpha}. The absence of ERR{alpha} resulted in a decrease in citrate synthase enzyme activity in response to PGC-1{alpha} overexpression. Our results indicate an essential role for ERR{alpha} as a key regulator of oxidative metabolism.},
doi = {10.1016/j.bbrc.2007.03.126},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 357,
place = {United States},
year = {Fri May 25 00:00:00 EDT 2007},
month = {Fri May 25 00:00:00 EDT 2007}
}
  • Estrogen-related receptor {alpha} (ERR{alpha}) is an orphan nuclear receptor that regulates cellular energy metabolism by modulating gene expression involved in fatty acid oxidation and mitochondrial biogenesis in brown adipose tissue. However, the physiological role of ERR{alpha} in adipogenesis and white adipose tissue development has not been well studied. Here, we show that ERR{alpha} and ERR{alpha}-related transcriptional coactivators, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator-1{alpha} (PGC-1{alpha}) and PGC-1{beta}, can be up-regulated in 3T3-L1 preadipocytes at mRNA levels under the adipogenic differentiation condition including the inducer of cAMP, glucocorticoid, and insulin. Gene knockdown by ERR{alpha}-specific siRNA results in mRNA down-regulation of fatty acidmore » binding protein 4, PPAR{gamma}, and PGC-1{alpha} in 3T3-L1 cells in the adipogenesis medium. ERR{alpha} and PGC-1{beta} mRNA expression can be also up-regulated in another preadipocyte lineage DFAT-D1 cells and a pluripotent mesenchymal cell line C3H10T1/2 under the differentiation condition. Furthermore, stable expression of ERR{alpha} in 3T3-L1 cells up-regulates adipogenic marker genes and promotes triglyceride accumulation during 3T3-L1 differentiation. These results suggest that ERR{alpha} may play a critical role in adipocyte differentiation by modulating the expression of various adipogenesis-related genes.« less
  • No abstract prepared.
  • The identification and subsequent cloning of the 66-kDa human estrogen receptor (here termed hER-{alpha}66), its 46-kDa splice variant hER-{alpha}46, and the closely related hER-{beta} have had a profound impact on the generation of new understanding of estrogen-mediated functions and led to progress in diagnosis and treatment of human breast cancer. However, a persistent problem has been that not all findings previously reported in estrogen-stimulated cell proliferation can be explained through the known properties of the different estrogen receptors described. As the consequence of a search for alternative mechanisms to account for these different findings, we have now identified, cloned, andmore » expressed in HEK 293 cells a previously unrecognized 36-kDa variant of hER-{alpha}66, termed hER-{alpha}36. hER-{alpha}36 differs from hER-{alpha}66 since it lacks both transcriptional activation domains (AF-1 and AF-2) but it retains the DNA-binding domain, and partial dimerization and ligand-binding domains of hER-{alpha}66. It also contains three myristoylation sites postulated to direct ER-{alpha}36 to the plasma membrane. It is concluded that ER-{alpha}36 is a unique variant of ER-{alpha}66; ER-{alpha}36 is predicted to function as a dominant-negative effector of hER-{alpha}66-mediated estrogen-responsive gene pathways and has the potential to trigger membrane-initiated mitogenic estrogen signaling.« less
  • Estrogen receptor-related receptor gamma (ERR{gamma}) is a member of the nuclear receptor family of transcriptional activators. To date, the target genes and physiological functions of ERR{gamma} are not well understood. In the current study, we identify that Plk2 is a novel target of ERR{gamma}. Northern blot analysis showed that overexpression of ERR{gamma} induced Plk2 expression in cancer cell lines. ERR{gamma} activated the Plk2 gene promoter, and deletion and mutational analysis of the Plk2 promoter revealed that the ERR{gamma}-response region is located between nucleotides (nt) -2327 and -2229 and -441 and -432 (relative to the transcriptional start site at +1). Electrophoreticmore » mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis demonstrated that ERR{gamma} binds directly to the Plk2 promoter. Overexpression of ERR{gamma} in the presence of the mitotic inhibitor nocodazole significantly decreased apoptosis, and induced S-phase cell cycle progression through the induction of Plk2 expression. Taken together, these results demonstrated that Plk2 is a novel target of ERR{gamma}, and suggest that this interaction is crucial for cancer cell proliferation.« less
  • We previously showed that ginsenosides increase nitric oxide (NO) production in vascular endothelium and that ginsenoside Rg3 (Rg3) is the most active one among ginseng saponins. However, the mechanism for Rg3-mediated nitric oxide production is still uncertain. In this study, we determined whether Rg3 affects phosphorylation and expression of endothelial nitric oxide synthase (eNOS) in ECV 304 human endothelial cells. Rg3 increased both the phosphorylation and the expression of eNOS in a concentration-dependent manner and a maximal effect was found at 10 {mu}g/ml of Rg3. The enzyme activities of phosphatidylinositol 3-kinase (PI3-kinase), c-Jun N-terminal kinase (JNK), and p38 kinase weremore » enhanced as were estrogen receptor (ER)- and glucocorticoid receptor (GR)-dependent reporter gene transcriptions in Rg3-treated endothelial cells. Rg3-induced eNOS phosphorylation required the ER-mediated PI3-kinase/Akt pathway. Moreover, Rg3 activates AMP-activated protein kinase (AMPK) through up-regulation of CaM kinase II and Rg3-stimulated eNOS phosphorylation was reversed by AMPK inhibition. The present results provide a mechanism for Rg3-stimulated endothelial NO production.« less