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Modulation of androgen receptor transcriptional activity by the estrogen receptor
M V Kumar1, M E Leo, D J Tindall
1Department of Urology Research, Mayo Foundation, Rochester, Minnesota.
Abstract:
Estrogen/androgen receptor interactions in naturally occurring physiological systems and the effect of their respective steroid hormones on transcriptional activity remain undefined. In an attempt to delineate further the nature of the interaction between these two steroid hormone receptors we have examined the effect of cotransfection of androgen (AR) and estrogen receptor (ER) cDNAs on the expression of the mouse mammary tumor virus long terminal repeat region (MMTV-LTR) linked to the chloramphenicol-acetyltransferase (CAT) reporter gene. In QT6 cells, which contain neither AR nor ER, cotransfection of AR cDNA with the MMTV-LTR-CAT reporter, resulted in transactivation only in the presence of dihydrotestosterone (DHT). Treatment with 10(-8) M each of estradiol-17 beta (E2), dexamethasone, or progesterone did not enhance CAT activity, whereas treatment with the androgens DHT and mibolerone resulted in 87% and 89% CAT activity. Transfection of increasing concentrations of ER cDNA in the presence of 100 ng of AR cDNA and 10(-8) M each of DHT and E2 showed a dose-dependent decrease in CAT activity as compared to the response with DHT alone. Cotransfection of AR and ER cDNA in the presence of 10(-8) M DHT and increasing concentrations of E2 resulted in a dose-dependent decrease in CAT activity. When cells were treated with increasing concentrations of DHT with 10(-8) M E2 no significant increase in CAT activity was observed. In GC cells, which contain endogenous ER but no AR, cotransfection of AR cDNA and treatment with E2 and DHT, also reduced DHT-induced CAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Estrogen receptor (ER) cotransfection with androgen receptor (AR) cDNA inhibits AR-mediated transcriptional activity, even with androgens present. This suggests a direct inhibitory interaction between ER and AR in regulating gene expression.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Estrogen receptor (ER) and androgen receptor (AR) interactions and their effects on transcriptional activity are not fully understood.
- Steroid hormone receptor crosstalk influences gene expression.
Purpose of the Study:
- To investigate the interaction between ER and AR.
- To determine the effect of ER cotransfection on AR-mediated transcriptional activity.
Main Methods:
- Cotransfection of AR and ER cDNAs with the mouse mammary tumor virus long terminal repeat (MMTV-LTR) linked to a chloramphenicol-acetyltransferase (CAT) reporter gene in QT6 and GC cells.
- Treatment with various steroid hormones including dihydrotestosterone (DHT) and estradiol-17 beta (E2).
- Dose-dependent analysis of receptor cDNA concentrations and hormone treatments.
Main Results:
- AR-mediated transactivation of MMTV-LTR-CAT was observed only with androgens like DHT.
- Cotransfection of ER cDNA dose-dependently decreased AR-mediated CAT activity in the presence of DHT and E2.
- E2 treatment did not enhance AR-mediated activity, and increasing E2 concentrations further reduced it.
Conclusions:
- Estrogen receptor directly inhibits androgen receptor-mediated transcriptional activity.
- ER and AR interactions can modulate gene expression in a complex manner.
- Further research is needed to elucidate the precise mechanisms of ER/AR crosstalk.