Document Detail

Aromatase promoter I.f is regulated by estrogen receptor alpha (ESR1) in mouse hypothalamic neuronal cell lines.
MedLine Citation:
PMID:  19605792     Owner:  NLM     Status:  MEDLINE    
Aromatase (CYP19A1) catalyzes the conversion of C(19) steroids to estrogens. Aromatase and its product estradiol (E(2)) are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The regulation of aromatase expression in the brain is not well understood. The aromatase (Cyp19a1) gene is selectively expressed in distinct neurons of the hypothalamus through a distal brain-specific promoter I.f located approximately 36 kb upstream of the coding region. Here, we investigated a short feedback effect of E(2) on aromatase mRNA expression and enzyme activity using estrogen receptor alpha (ESR1; also known as ER alpha)-positive or ESR1-negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. Estradiol regulated aromatase mRNA expression and enzyme activity in a time- and dose-dependent manner, whereas an E(2) antagonist reversed these effects. The nucleotide -200/-1 region of promoter I.f conferred E(2) responsiveness. Two activator protein 1 (AP-1) elements in this region were essential for induction of promoter activity by E(2). ESR1 and JUN (c-Jun) bound to these AP-1 motifs in intact cells and under cell-free conditions. The addition of an ESR1 mutant that interacts with JUN but not directly with DNA enhanced E(2)-dependent promoter I.f activity. Independently, we demonstrated an interaction between ESR1 and JUN in hypothalamic cells. Knockdown of ESR1 abolished E(2)-induced aromatase mRNA and enzyme activity. Taken together, E(2) regulates Cyp19a1 expression via promoter I.f by enhanced binding of an ESR1/JUN complex to distinct AP-1 motifs in hypothalamic cells. We speculate that this mechanism may, in part, regulate gonadotropin secretion and sexual activity.
M Bertan Yilmaz; Andrew Wolfe; You-Hong Cheng; Christine Glidewell-Kenney; J Larry Jameson; Serdar E Bulun
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-07-15
Journal Detail:
Title:  Biology of reproduction     Volume:  81     ISSN:  1529-7268     ISO Abbreviation:  Biol. Reprod.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-29     Completed Date:  2009-12-16     Revised Date:  2014-07-02    
Medline Journal Info:
Nlm Unique ID:  0207224     Medline TA:  Biol Reprod     Country:  United States    
Other Details:
Languages:  eng     Pagination:  956-65     Citation Subset:  IM    
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MeSH Terms
Analysis of Variance
Aromatase / genetics,  metabolism*
Blotting, Western
Cell Line
Cells, Cultured
Chromatin Immunoprecipitation
Dose-Response Relationship, Drug
Electrophoretic Mobility Shift Assay
Enzyme Assays
Estradiol / analogs & derivatives,  pharmacology
Estrogen Antagonists / pharmacology
Estrogen Receptor alpha / metabolism*
Estrogens / pharmacology
Hypothalamus / cytology,  drug effects,  metabolism*
Neurons / cytology,  drug effects,  metabolism*
Promoter Regions, Genetic / genetics,  physiology*
Proto-Oncogene Proteins c-fos / genetics,  metabolism
Proto-Oncogene Proteins c-jun / genetics,  metabolism
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Transcription Factor AP-1 / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Estrogen Antagonists; 0/Estrogen Receptor alpha; 0/Estrogens; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Transcription Factor AP-1; 22X328QOC4/fulvestrant; 4TI98Z838E/Estradiol; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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