The subdomains of the transactivation domain of the aryl hydrocarbon receptor (AhR) inhibit AhR and estrogen receptor transcriptional activity

ABSTRACT The ubiquitin-proteasome pathway has emerged as an important regulatory mechanism governing the activity of several transcription factors. While estrogen receptor α (ERα) is also subjected to rapid ubiquitin-proteasome degradation, the relationship between proteolysis and transcriptional regulation is incompletely understood. Based on studies primarily focusing on the C-terminal ligand-binding and AF-2 transactivation domains, an assembly of an active transcriptional complex has been proposed to signal ERα proteolysis that is in turn necessary for its transcriptional activity. Here, we investigated the role of other regions of ERα and identified S118 within the N-terminal AF-1 transactivation domain as an additional element for regulating estrogen-induced ubiquitination and degradation of ERα. Significantly, different S118 mutants revealed that degradation and transcriptional activity of ERα are mechanistically separable functions of ERα. We find that proteolysis of ERα correlates with the ability of ERα mutants to recruit specific ubiquitin ligases regardless of the recruitment of other transcription-related factors to endogenous model target genes. Thus, our findings indicate that the AF-1 domain performs a previously unrecognized and important role in controlling ligand-induced receptor degradation which permits the uncoupling of estrogen-regulated ERα proteolysis and transcription.

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Cross-Talk in the Female Rat Mammary Gland: Influence of Aryl Hydrocarbon Receptor on Estrogen Receptor Signaling

Environmental Health Perspectives ◽

10.1289/ehp.1509680 ◽

2016 ◽

Vol 124 (5) ◽

pp. 601-610 ◽

Cited By ~ 12

Author(s):

Janina Helle ◽

Manuela I. Bader ◽

Annekathrin M. Keiler ◽

Oliver Zierau ◽

Günter Vollmer ◽

...

Keyword(s):

Estrogen Receptor ◽

Mammary Gland ◽

Aryl Hydrocarbon Receptor ◽

Cross Talk ◽

Female Rat ◽

Receptor Signaling ◽

Aryl Hydrocarbon ◽

Estrogen Receptor Signaling ◽

Rat Mammary Gland

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Reactivation of Estrogen Receptor α by Vorinostat Sensitizes Mesenchymal-Like Triple-Negative Breast Cancer to Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor

PLoS ONE ◽

10.1371/journal.pone.0074525 ◽

2013 ◽

Vol 8 (9) ◽

pp. e74525 ◽

Cited By ~ 24

Author(s):

Karri Stark ◽

Angelika Burger ◽

Jianmei Wu ◽

Phillip Shelton ◽

Lisa Polin ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Aryl Hydrocarbon Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Estrogen Receptor Α ◽

Aryl Hydrocarbon

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The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

International Journal of Breast Cancer ◽

10.4061/2011/923250 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 23

Author(s):

Mariana A. Callero ◽

Andrea I. Loaiza-Pérez

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Aryl Hydrocarbon Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Antitumor Agents ◽

Breast Cancers ◽

Nude Mouse Model ◽

Aryl Hydrocarbon ◽

Mcf 7

Many estrogen-receptor- (ER-) expressing breast cancers become refractory to ER-based therapies. New antitumor drugs like aminoflavone (AF) and benzothiazoles (Bzs) have been developed and have exquisite antitumor activity in ER+MCF-7 and T47D cells and in a MCF-7 nude mouse model. ER(−) breast cancer cells like MDA-MB-231 are less susceptible. We previously found in MCF-7 cells that these drugs activate the aryl hydrocarbon receptor (AhR) via translocation to the nucleus, induction of AhR-specific DNA binding activity, and expression of CYP1A1, whose transcription is controlled by the AhR-ARNT transcription factor. CYP1A1 metabolizes AF and Bz to a species which directly or after further metabolism damages DNA. In contrast an AhR-deficient variant of MCF-7 or cells with predominantly nuclear AhR expression, such as MDA-MB 231, are resistant. Thus, these drugs, unlike other neoplastic agents, require AhR-mediated signaling to cause DNA damage. This is a new treatment strategy for breast cancers with intact AhR signaling.

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