Document Detail

Estrogen receptor alpha, fos-related antigen-2, and c-Jun coordinately regulate human UDP glucuronosyltransferase 2B15 and 2B17 expression in response to 17beta-estradiol in MCF-7 cells.
MedLine Citation:
PMID:  19487245     Owner:  NLM     Status:  MEDLINE    
UDP-glucuronosyltransferase 2B15 and 2B17 expression is up-regulated by 17beta-estradiol in MCF-7 breast cancer cells, as assessed by quantitative real-time polymerase chain reaction. Using 5'-deletion mapping and site-directed mutagenesis, we demonstrate that 17beta-estradiol activation of UGT2B15 gene transcription is mediated by a 282-base pair fragment positioned -454 to -172 nucleotides from the translation start site. This region contains two putative activator protein-1 (AP-1) elements, one imperfect estrogen response element (ERE), and two consensus ERE half-sites. We propose that these five sites act as an estrogen response unit (ERU), because mutation in any site reduces activation of the UGT2B15 promoter by 17beta-estradiol. Despite the presence of two AP-1 elements, the UGT2B15 promoter is not responsive to the AP-1 activator phorbol 12-myristate 13-acetate. Although electrophoretic mobility shift assays (EMSA) indicate that the AP-1 proteins c-Jun and Fos-related antigen 2 (Fra-2) bound to the distal AP-1 site, binding of Jun or Fos family members to the proximal AP-1 site was not detected by EMSA. Chromatin immunoprecipitation assays showed a 17beta-estradiol-induced recruitment of estrogen receptor (ER) alpha, c-Jun, and Fra-2 to the 282-bp ERU. The involvement of these three transcription factors in the stimulation of UGT2B15 gene expression by 17beta-estradiol was confirmed by siRNA silencing experiments. Mutagenesis and siRNA experiments indicate that UGT2B17 expression is also regulated by 17beta-estradiol via the ERU, which is fully conserved in both promoters. Because UGT2B15 and UGT2B17 inactivate steroid hormones by glucuronidation, the regulation of their genes by 17beta-estradiol may maintain steroid hormone homeostasis and prevent excessive estrogen signaling activity.
Dong Gui Hu; Peter I Mackenzie
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-01
Journal Detail:
Title:  Molecular pharmacology     Volume:  76     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-21     Completed Date:  2009-08-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  425-39     Citation Subset:  IM    
Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park, SA, Australia.
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MeSH Terms
Breast Neoplasms / metabolism
Cell Line, Tumor
Estradiol / pharmacology*
Estrogen Receptor alpha / genetics,  metabolism*
Fos-Related Antigen-2 / genetics,  metabolism*
Gene Expression Regulation*
Glucuronosyltransferase / genetics,  metabolism*
Proto-Oncogene Proteins c-jun / genetics,  metabolism*
Reg. No./Substance:
0/Estrogen Receptor alpha; 0/Fos-Related Antigen-2; 0/Proto-Oncogene Proteins c-jun; 50-28-2/Estradiol; EC; EC 2B15, human

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