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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN
*ESTRADIOL
Molecular Endocrinology 13 (9): 1511-1521
Copyright © 1999 by The Endocrine Society

Transcriptional Activation of c-fos Protooncogene by 17ß-Estradiol: Mechanism of Aryl Hydrocarbon Receptor-Mediated Inhibition

Renqin Duan, Weston Porter, Ismael Samudio, Carrie Vyhlidal, Michael Kladde and Stephen Safe

Department of Veterinary Physiology and Pharmacology (R.D., W.P., I.S., S.S.) and Department of Biochemistry and Biophysics (C.V., M.K.) Texas A&M University College Station, Texas 77843

17ß-Estradiol (E2) induced c-fos protooncogene mRNA levels in MCF-7 human breast cancer cells, and maximal induction was observed within 1 h after treatment. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibited the E2-induced response within 2 h. The molecular mechanism of this response was further investigated using pFC2-CAT, a construct containing a -1400 to +41 sequence from the human c-fos protooncogene linked to a bacterial chloramphenicol acetyltransferase (CAT) reporter gene. In MCF-7 cells transiently transfected with pFC2-CAT, 10 nM E2 induced an 8.5-fold increase of CAT activity, and cotreatment with 10 nM TCDD decreased this response by more than 45%. {alpha}-Naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist, blocked the inhibitory effects of TCDD; moreover, the inhibitory response was not observed in variant Ah-nonresponsive MCF-7 cells, suggesting that the AhR complex was required for estrogen receptor cross-talk. The E2-responsive sequence (-1220 to -1155) in the c-fos gene promoter contains two putative core pentanucleotide dioxin-responsive elements (DREs) at -1206 to -1202 and -1163 to -1159. In transient transfection assays using wild-type and core DRE mutant constructs, the downstream core DRE (at -1163 to -1159) was identified as a functional inhibitory DRE. The results of photo-induced cross-linking, gel mobility shift, and in vitro DNA footprinting assays showed that the AhR complex interacted with the core DRE that also overlapped the E2-responsive GC-rich site (-1168 to -1161), suggesting that the mechanism for AhR-mediated inhibitory effects may be due to quenching or masking at the Sp1-binding site.




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