The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress.
The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress.
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DOI：
10.1038/cddis.2010.9
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发表时间：
2010
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
我们之前发现了一种新的雌激素诱导基因EIG 121，在子宫内膜样和非子宫内膜样子宫内膜癌中受到差异调节。EIG 121的功能尚不清楚。使用四环素诱导的系统，我们发现，过度表达的EIG 121，但不是LacZ，引起了深刻的抑制细胞生长。亚细胞分离和免疫荧光标记表明，EIG 121是一个跨膜蛋白定位于质膜-晚期内体-溶酶体室。假定的跨膜结构域的删除废除了膜协会。在过度表达EIG 121的细胞中，EIG 121诱导后细胞质空泡积累，自噬体标记物LC 3易位成点状、点状结构。电子显微镜显示，在细胞过度表达EIG 121，自噬体显着增加。EIG 121的过表达还增加了含有酸性囊泡的细胞，并诱导溶酶体降解长寿命蛋白。在MCF-7细胞中，EIG 121和LC 3在饥饿后通过溶酶体机制迅速降解。敲除EIG 121阻断饥饿诱导的LC 3降解。EIG 121的敲低本身不影响细胞存活。当与饥饿或细胞毒性剂结合时，EIG 121敲低大大增加了细胞凋亡。我们的研究结果表明EIG 121与内体-溶酶体区室相关，并且可能在自噬中起重要作用。在饥饿和暴露于细胞毒性剂等不利条件下，EIG 121可通过上调自噬途径保护细胞免于细胞死亡。
We previously identified a novel estrogen-induced gene, EIG121, as being differentially regulated in endometrioid and nonendometrioid endometrial carcinoma. The function of EIG121 was unknown. Using a tetracycline-inducible system, we found that overexpression of EIG121, but not of LacZ, caused a profound suppression of cell growth. Subcellular fractionation and immunofluroscent labeling indicated that EIG121 was a transmembrane protein localized in the plasma membrane-late endosome–lysosome compartments. Deletion of the putative transmembrane domain abolished the membrane association. In cells overexpressing EIG121, cytoplasmic vacuoles accumulated after EIG121 induction, and the autophagosome marker LC3 translocated into punctuate, dot-like structures. Electron microscopy revealed that in cells overexpressing EIG121, autophagosomes were markedly increased. Overexpression of EIG121 also increased the cells containing acidic vesicles and induced lysosomal degradation of long-lived proteins. In MCF-7 cells, both EIG121 and LC3 were rapidly degraded by a lysosomal mechanism after starvation. Knockdown of EIG121 blocked starvation-induced LC3 degradation. By itself, knockdown of EIG121 did not affect cell survival. When combined with starvation or cytotoxic agents, EIG121 knockdown greatly increased apoptosis. Our results suggest that EIG121 is associated with the endosome–lysosome compartments and may have an important role in autophagy. Under unfavorable conditions such as starvation and exposure to cytotoxic agents, EIG121 may protect cells from cell death by upregulating the autophagy pathway.
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