Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP.
Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP.
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DOI：
10.1042/bj20111890
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Dong JT
中科院分区：
文献类型：
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作者：
Dong XY;Fu X;Fan S;Guo P;Su D;Dong JT
我们之前发现肿瘤抑制因子ATBF1与雌激素erα信号形成一个自我调节反馈回路，以调节乳腺癌细胞中雌激素依赖性细胞的增殖。在这个循环中，ATBF1抑制雌激素- er - α信号的功能，而ATBF1蛋白水平通过雌激素诱导的转录上调以及泛素蛋白酶体途径（UPP）介导的蛋白降解而被微调。在这里，我们发现雌激素反应指蛋白（EFP）是一种E3泛素连接酶，介导雌激素诱导的ATBF1蛋白降解。EFP敲低可增加ATBF1蛋白水平，但过表达可降低ATBF1蛋白水平。EFP与ATBF1蛋白相互作用并泛素化。此外，我们发现EFP是雌激素诱导的ATBF1蛋白降解的一个重要因素，其他一些因素也参与其中。在人原发性乳腺肿瘤中，由于两者都是直接上调的ERα靶基因产物，ATBF1蛋白水平与EFP蛋白水平呈正相关。然而，ATBF1蛋白与EFP蛋白的比值与EFP蛋白水平呈负相关。功能上，ATBF1可拮抗efp介导的细胞增殖。这些发现不仅证实了EFP是雌激素诱导的ATBF1蛋白降解的E3泛素连接酶，而且进一步支持了ATBF1与雌激素- er - α信号传导之间的自调节反馈回路，从而暗示了ATBF1参与雌激素依赖性乳腺发育和致癌。
We previously revealed that tumor suppressor ATBF1 formed an autoregulatory feedback loop with estrogen-ERα signaling to regulate estrogen-dependent cell proliferation in breast cancer cells. In this loop, ATBF1 inhibits the function of estrogen-ERα signaling while ATBF1 protein levels are fine-tuned by estrogen-induced transcriptional upregulation as well as ubiquitin proteasome pathway (UPP)-mediated protein degradation. Here we show that the estrogen-responsive finger protein (EFP) is an E3 ubiquitin ligase mediating estrogen-induced ATBF1 protein degradation. Knockdown increases but overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in estrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumors, due to both as directly-upregulated ERα target gene products, the levels of ATBF1 protein are positively correlated with the levels of EFP protein. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for estrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and estrogen-ERα signaling and thus implicate ATBF1 in estrogen-dependent breast development and carcinogenesis.