Estrogen Receptor Biology
Christina T. Teng, Ph.D.
Tel (919) 541-0344
Fax (919) 541-1978
email@example.com P.O. Box 12233
Mail Drop E2-01
Research Triangle Park, North Carolina 27709
The primary goal of the Gene Regulation Group is to elucidate the molecular events associated with the regulation of gene expression by an estrogen receptor (ER)-mediated mechanism.
Nuclear receptors are a family of transcription factors that play a pivotal role in the proper development and homeostatic maintenance of normal physiological functions. Environmental endocrine disruptors such as synthetic chemicals often target nuclear receptors, especially steroid receptors. These environmental agents interfere with the expression and function of nuclear receptors, and thus have serious health consequences. To address the question of how environmental agents interfere with the function of nuclear receptors, researchers need to understand the intricate molecular events associated with gene expression under the influence of these nuclear receptors.
The group uses the regulation of the lactoferrin gene as a model for studying the molecular mechanism of estrogen action. Lactoferrin is an iron binding secretory glycoprotein that kills bacteria and inhibits viral infection. It also has a broad range of effects on immune and inflammatory responses. The lactoferrin gene has been shown to be sensitive to estrogens, xenoestrogens and catecholestrogena, retinoic acid, glucocorticoid, forskolin and EGF. Deregulation of lactoferrin gene expression has been associated with tumors, cancer, a weakened immune system and polygenic infections. Group members have characterized the estrogen response element and the element responsible for mitogen stimulation of the lactoferrin gene. During the course of these studies, the estrogen-related receptor alpha (ERRα) was cloned and the results demonstrated that ERRα binds to an element (ERRE) of the lactoferrin gene, which influences estrogen responsiveness.
The ERRα modulates estrogen response either positively or negatively depending on promoter context and the cellular environment. Since ERRs and ERs are very close in sequence homology, they recognize the same response element and coactivators of the target genes, which result in a competitive inhibition to each other’s activity. Conversely, ERRs can actually synergize with ERs during estrogen response, as is the case with the lactoferrin gene. Recent evidence demonstrates that ERRα up-regulates a set of genes involved in mitochondria oxidative phosphorylation and mitochondria biogenesis when the demand for energy production is increased. Additionally, ERRα regulates the expression of the monoamine oxidase (MAOs) gene and the epithelial nitro oxide synthase (eNOS) gene which participates in neurotransmitter degradation and in NO production in epithelial cells, respectively. To understand the in vivo function of ERRα, the Gene Regulation Group is in the process of producing an ERRα-null (ERRα KO) and an ERRα-floxed mouse. The generation of an ERRα KO or tissue specific ERRα-null mouse will be especially useful since the receptor is active without a ligand. Since ERRα is constitutively active, regulation of its expression could be important in affecting the biological roles it plays. Studies from this group have shown that estrogen stimulates ERRα gene expression in mouse uterus and a 34bp DNA element that contains multiple steroid hormone response element half-sites (MHREs) of the gene is responsible for the estrogen stimulation. Furthermore, MHREs mediate the stimulation via an inducible peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and estrogen related receptor γ (ERRγ). These studies have demonstrated that regulation of ERRα gene expression through common MHREs is highly complex.
As mentioned above, ERRα plays an important role in energy metabolism and may have far reaching implications. At the present, approximately 30.5% of the American population is obese. Genetic background, lifestyle and imbalanced energy intake and expenditure are all contributors to this condition. Excess weight significantly increases the risk of heart disease, high blood pressure, stroke, diabetes, infertility, gall-bladder disease, osteoarthritis and many forms of cancer. Therefore, better understanding of ERRα function and regulation using both in vitro and in vivo models will provide a foundation in the development of drug therapy for intervention and prevention of metabolic related disease such as heart disease, diabetes and cancer.
Major areas of research:
Christina Teng, Ph.D., leads the Gene Regulation Group within the Laboratory of Reproductive and Developmental Toxicology. She received her Ph.D. in 1969 at University of Texas, Austin, Texas. She has published 83 peer-reviewed articles in leading biomedical journals as well as 17 book chapters. She served as an Assistant Professor at the Department of Cell Biology, Baylor College of Medicine, Houston, Texas before joining NIEHS in 1983.