Nuclear tristetraprolin acts as a corepressor of multiple steroid nuclear receptors in breast cancer cells.
Nuclear tristetraprolin acts as a corepressor of multiple steroid nuclear receptors in breast cancer cells.
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DOI：
10.1016/j.ymgmr.2016.02.004
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发表时间：
2016-06
影响因子：
1.9
通讯作者：
León-Del-Río A
中科院分区：
文献类型：
--
作者：
Barrios-García T;Gómez-Romero V;Tecalco-Cruz Á;Valadéz-Graham V;León-Del-Río A
Tristetraprolin（TTP）是一种34 kDa的含锌指的因子，在哺乳动物细胞中通过两种不同的机制作为肿瘤抑制蛋白。在细胞质中，TTP促进数百种编码参与炎症、组织侵袭和转移的细胞因子的mRNA的衰变。在细胞核中，TTP已被鉴定为雌激素受体α（ERα）的转录辅阻遏物，其与大多数乳腺癌肿瘤的发生和进展相关。在这项工作中，我们报告，核TTP调节孕激素受体（PR），糖皮质激素受体（GR）和雄激素受体（AR）的反式激活活性。近年来，这些类固醇核受体已被证明在乳腺癌的临床和治疗相关性。TTP与类固醇核受体之间的功能关联得到了TTP与ERα、PR、GR和AR在体内物理相互作用的发现的支持。我们还表明，TTP过表达减弱了所有测试的类固醇核受体的反式激活。相反，siRNA介导的MCF-7细胞内源性TTP表达的降低导致ERα、PR、GR和AR的转录活性增加。这些结果提示，核TTP在乳腺癌细胞中的功能是作为ERα、PR、GR和AR的辅助抑制因子。我们认为，在不同类型的乳腺癌肿瘤中观察到的TTP表达的减少可能有助于这种疾病的发展，通过产生多种类固醇核受体的反式激活活性的失调。
Tristetraprolin (TTP) is a 34-kDa, zinc finger-containing factor that in mammalian cells acts as a tumor suppressor protein through two different mechanisms. In the cytoplasm TTP promotes the decay of hundreds of mRNAs encoding cell factors involved in inflammation, tissue invasion, and metastasis. In the cell nucleus TTP has been identified as a transcriptional corepressor of the estrogen receptor alpha (ERα), which has been associated to the development and progression of the majority of breast cancer tumors. In this work we report that nuclear TTP modulates the transactivation activity of progesterone receptor (PR), glucocorticoid receptor (GR) and androgen receptor (AR). In recent years these steroid nuclear receptors have been shown to be of clinical and therapeutical relevance in breast cancer. The functional association between TTP and steroid nuclear receptors is supported by the finding that TTP physically interacts with ERα, PR, GR and AR in vivo. We also show that TTP overexpression attenuates the transactivation of all the steroid nuclear receptors tested. In contrast, siRNA-mediated reduction of endogenous TTP expression in MCF-7 cells produced an increase in the transcriptional activities of ERα, PR, GR and AR. Taken together, these results suggest that the function of nuclear TTP in breast cancer cells is to act as a corepressor of ERα, PR, GR and AR. We propose that the reduction of TTP expression observed in different types of breast cancer tumors may contribute to the development of this disease by producing a dysregulation of the transactivation activity of multiple steroid nuclear receptors.