A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase
A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase
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DOI：
10.1128/mcb.00630-16
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发表时间：
2017-07-01
影响因子：
5.3
通讯作者：
Poellinger, Lorenz
中科院分区：
文献类型：
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作者：
Luecke-Johansson, Sandra;Gralla, Michael;Poellinger, Lorenz
芳烃受体（AhR）是一种配体激活的转录因子，被称为毒性反应的介体。最近，研究表明AhR具有双重功能。除了作为转录因子外，它还具有内在的E3泛素连接酶功能，其靶向，例如，蛋白酶体降解的类固醇受体。本研究的目的是确定决定AhR是否作为转录因子或E3泛素连接酶的分子开关。为了做到这一点，我们使用了乳腺癌细胞系MCF 7，它表达了一种功能性雌激素受体α（ER α）信号通路。我们的数据表明，芳烃受体核转运蛋白（ARNT）在调节AhR的双重功能中起着重要作用。ARNT敲低显着损害配体激活的AhR的转录激活特性，但不影响其E3泛素连接酶功能。ARNT本身的可用性由另一种碱性螺旋-环-螺旋（bHLH）-PerARNT-SIM（PAS）蛋白（AhR功能的阻遏物（AhRR））调节。过表达AhRR的MCF 7细胞表现出较低的ER α蛋白水平，对雌二醇的反应性降低，生长速率降低。重要的是，当这些细胞用于在SCID小鼠中产生雌激素依赖性异种移植肿瘤时，我们还观察到较低的ER α蛋白水平和减小的肿瘤质量，这意味着AhR在MCF 7异种移植肿瘤中具有肿瘤抑制样功能。
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is known as a mediator of toxic responses. Recently, it was shown that the AhR has dual functions. Besides being a transcription factor, it also possesses an intrinsic E3 ubiquitin ligase function that targets, e.g., the steroid receptors for proteasomal degradation. The aim of this study was to identify the molecular switch that determines whether the AhR acts as a transcription factor or an E3 ubiquitin ligase. To do this, we used the breast cancer cell line MCF7, which expresses a functional estrogen receptor alpha (ER alpha) signaling pathway. Our data suggest that aryl hydrocarbon receptor nuclear translocator (ARNT) plays an important role in the modulation of the dual functions of the AhR. ARNT knockdown dramatically impaired the transcriptional activation properties of the ligand-activated AhR but did not affect its E3 ubiquitin ligase function. The availability of ARNT itself is modulated by another basic helix-loop-helix (bHLH)-PerARNT- SIM (PAS) protein, the repressor of AhR function (AhRR). MCF7 cells overexpressing the AhRR showed lower ER alpha protein levels, reduced responsiveness to estradiol, and reduced growth rates. Importantly, when these cells were used to produce estrogendependent xenograft tumors in SCID mice, we also observed lower ER alpha protein levels and a reduced tumor mass, implying a tumor-suppressive-like function of the AhR in MCF7 xenograft tumors.