Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress.
Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress.
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DOI：
10.1038/onc.2011.87
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发表时间：
2011-08-25
期刊：
影响因子：
8
通讯作者：
Zhang, X. D.
中科院分区：
文献类型：
--
作者：
Dong, L.;Jiang, C. C.;Thorne, R. F.;Croft, A.;Yang, F.;Liu, H.;de Bock, C. E.;Hersey, P.;Zhang, X. D.
过去的研究表明，抗凋亡蛋白Bcl2家族蛋白Mcl-1的上调是黑色素瘤细胞对内质网(ER)应激的主要适应机制，在黑色素瘤细胞抵抗细胞凋亡中具有重要作用。在这项研究中，我们证明了由药理内质网应激诱导剂触发的黑色素瘤细胞Mcl-1转录增加是由转录因子Ets-1介导的。通过对McL-1启动子的增量缺失分析，我们发现了一个含有Ets-1结合位点的DNA片段，该DNA片段在转录水平上对内质网应激有反应。Ets-1结合位点的突变或Ets-1的敲除抑制了Mcl-1的增加，表明Ets-1在Mcl-1的转录上调中起着关键作用。与Mcl-1类似，Ets-1在转录水平上受内质网应激上调。这是由IRE1α/XBP-1未折叠蛋白反应的分支介导的，因为在通过短发夹状α敲除建立的缺乏IRE1RNA或XBP-1的黑色素瘤细胞系中，Ets-1的上调受到抑制。XBP-1下游PI3K/Akt通路的激活也参与了该通路的抑制，从而阻断了Ets-1的上调。抑制Ets-1增强内质网应激诱导的黑色素瘤细胞系和新鲜黑色素瘤分离株中的细胞凋亡，概括了Mcl-1的抑制作用。这些结果揭示了内质网应激在黑色素瘤细胞中转录上调Mcl-1的关键机制，并确认Ets-1是抑制黑色素瘤细胞对凋亡敏感的潜在靶点。
Past studies have shown that upregulation of the anti-apoptotic Bcl-2 family protein Mcl-1 is a major adaptive mechanism of melanoma cells to endoplasmic reticulum (ER) stress, and has an important role in resistance of the cells to apoptosis. In this study, we show that the increase in transcription of Mcl-1 in melanoma cells triggered by pharmacological ER stress inducers is mediated by the transcription factor Ets-1. By incremental deletion analysis of the Mcl-1 promoter, we identified a DNA fragment containing an Ets-1 binding site that is transcriptionally responsive to ER stress. Mutations in the Ets-1 binding site or knockdown of Ets-1 inhibited the increase in Mcl-1, indicating that Ets-1 has a critical role in transcriptional upregulation of Mcl-1. Similar to Mcl-1, Ets-1 was transcriptionally upregulated by ER stress. This was mediated by the IRE1α/XBP-1 branch of the unfolded protein response, as upregulation of Ets-1 was inhibited in melanoma cell lines deficient in IRE1α or XBP-1 established by short hairpin RNA knockdown. Activation of the PI3k/Akt pathway downstream of XBP-1 was also involved, in that inhibition of the pathway blocked upregulation of Ets-1. Inhibition of Ets-1 enhanced ER stress-induced apoptosis in melanoma cell lines and in fresh melanoma isolates, recapitulating the effect of inhibition of Mcl-1. These results reveal a key mechanism by which Mcl-1 is transcriptionally upregulated in melanoma cells by ER stress, and identify Ets-1 as a potential target for inhibition to sensitize melanoma cells to apoptosis.
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