of Work: We have previously shown that estrogen-stimulated transcriptional activity of human lactoferrin gene in endometrium carcinoma cells, RL95-2, is mediated through a functional imperfect estrogen response element (iERE) present in the 5' flanking region of the gene. Upstream from the iERE, an extended steroid receptor half-site is protected by hERR a1 from DNase I digestion. From the electrophoresis mobility shift assay (EMSA), site-directed mutagenesis and DNA methylation interference analyses, we showed that binding of hERR a1 to the extended half-site of the steroid receptor enhances ER-mediated transcriptional activity of the human lactoferrin promoter. Mutation at the Gs in this region abolishes hERR a1 -DNA complex formation and reduces the estrogen responsiveness of the reporter plasmid containing the intact lactoferrin iERE. To examine the mechanism by which the hERR a1 and its DNA binding element enhance the estrogen response, we performed far-western and yeast two-hybrid analyses. The results showed that hERR1 interacted with estrogen receptor by direct protein-protein contact. Recently, we cloned and characterized the hERR a1 gene. By Fluorescent In-Situ Hybridization method (FISH), the hERRa gene was localized to the centromere region of chromosome 11q12. Partial sequencing, restriction mapping and PCR analysis revealed that the hERRa gene consists of seven exons and is over 20 kb in length. All intron/exon junctions follow the GT/AG rule. The highly conserved DNA binding domain of the hERRa1 is present in exon 2 and 3. Primer extension and RNase protection analyses reveal multiple transcription initiation sites in different human cell lines. The sequence immediately 5' of the transcriptional start sites of the hERRa1 message lacks a typical TATA box and CAAT box but is GC-rich and contains ten putative Sp1 binding sites. The region that contains the multiple Sp1 binding sites showed high levels of promoter activity when transiently transfected into the RL95-2 cells. We also isolated the cDNA of the mouse homologue of the hERRa and found that they share 97% homology in deduced amino acid sequence. Diethylstilbestrol (DES) stimulated the expression of ERR a mRNA in the uterus of 19-day-old mouse. We showed that DES but not progesterone or dexamethasone, enhanced the level of immunoreactive ERRa1 in the mouse uterus. These results demonstrated that hERRa modulates ER-stimulated activity by direct contact with the molecule and it is an estrogen responsive gene in the mouse uterus.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
Project #
Application #
Study Section
Special Emphasis Panel (LRDT)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Teng, Christina T; Li, Yin; Stockton, Pat et al. (2011) Fasting induces the expression of PGC-1? and ERR isoforms in the outer stripe of the outer medulla (OSOM) of the mouse kidney. PLoS One 6:e26961
Li, Yin; Birnbaumer, Lutz; Teng, Christina T (2010) Regulation of ERRalpha gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: differential molecular mechanisms mediated by g protein-coupled receptor GPR30/GPER-1. Mol Endocrinol 24:969-80
Li, Yin; Limmon, Gino V; Imani, Farhad et al. (2009) Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells. Biochimie 91:58-67
Wang, Liangli; Li, Yin; Hu, Peng et al. (2008) PGC-1 alpha induces dynamic protein interactions on the ERR alpha gene multi-hormone response element nucleosome in kidney cells. Biochem J :
Hu, Peng; Kinyamu, H Karimi; Wang, Liangli et al. (2008) Estrogen induces estrogen-related receptor alpha gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells. J Biol Chem 283:6752-63
Zhang, Zhiping; Teng, Christina T (2007) Interplay between estrogen-related receptor alpha (ERRalpha) and gamma (ERRgamma) on the regulation of ERRalpha gene expression. Mol Cell Endocrinol 264:128-41
Teng, Christina T; Gladwell, Wesley (2006) Single nucleotide polymorphisms (SNPs) in human lactoferrin gene. Biochem Cell Biol 84:381-4
Teng, Christina T (2006) Factors regulating lactoferrin gene expression. Biochem Cell Biol 84:263-7
Zhang, Zhiping; Chen, Kevin; Shih, Jean C et al. (2006) Estrogen-related receptors-stimulated monoamine oxidase B promoter activity is down-regulated by estrogen receptors. Mol Endocrinol 20:1547-61
Goldberg, Gary S; Kunimoto, Takehiko; Alexander, David B et al. (2005) Full length and delta lactoferrin display differential cell localization dynamics, but do not act as tumor markers or significantly affect the expression of other genes. Med Chem 1:57-64

Showing the most recent 10 out of 15 publications