The Stress Response Mediator ATF3 Represses Androgen Signaling by Binding the Androgen Receptor
The Stress Response Mediator ATF3 Represses Androgen Signaling by Binding the Androgen Receptor
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DOI：
10.1128/mcb.00159-12
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发表时间：
2012-08-01
影响因子：
5.3
通讯作者：
Yan, Chunhong
中科院分区：
文献类型：
--
作者：
Wang, Hongbo;Jiang, Ming;Yan, Chunhong
活化转录因子3（ATF 3）是细胞应激反应信号传导的常见介质，并且经常在前列腺癌中异常表达。我们在这里报告，ATF 3可以直接结合雄激素受体（AR），从而抑制AR介导的基因表达。ATF 3-AR相互作用需要ATF 3的亮氨酸拉链结构域，其独立地结合AR的DNA结合结构域和配体结合结构域，并且该相互作用防止AR结合到雄激素依赖性基因表达所需的顺式作用元件，同时抑制AR N-和C-末端相互作用。ATF 3表达缺失的功能后果包括前列腺癌细胞中雄激素依赖性基因转录增加，这与在含低雄激素培养基中生长的能力增加以及ATF 3敲除小鼠中前列腺上皮增殖活性增加相关，这与前列腺增生相关。因此，我们的研究结果表明，ATF 3是一种新型的雄激素信号转导抑制剂，可以抑制AR功能，使前列腺细胞恢复稳态，并在面对广泛的内在和环境损伤时保持完整性。
Activating transcription factor 3 (ATF3) is a common mediator of cellular stress response signaling and is often aberrantly expressed in prostate cancer. We report here that ATF3 can directly bind the androgen receptor (AR) and consequently repress AR-mediated gene expression. The ATF3-AR interaction requires the leucine zipper domain of ATF3 that independently binds the DNA-binding and ligand-binding domains of AR, and the interaction prevents AR from binding to cis-acting elements required for expression of androgen-dependent genes while inhibiting the AR N- and C-terminal interaction. The functional consequences of the loss of ATF3 expression include increased transcription of androgen-dependent genes in prostate cancer cells that correlates with increased ability to grow in low-androgen-containing medium and increased proliferative activity of the prostate epithelium in ATF3 knockout mice that is associated with prostatic hyperplasia. Our results thus demonstrate that ATF3 is a novel repressor of androgen signaling that can inhibit AR functions, allowing prostate cells to restore homeostasis and maintain integrity in the face of a broad spectrum of intrinsic and environmental insults.