Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition
Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition
复制标题
DOI：
10.1182/blood-2011-07-366492
复制
发表时间：
2012-01-19
期刊：
影响因子：
20.3
通讯作者：
Vanderkerken, Karin
中科院分区：
文献类型：
--
作者：
Hu, Jinsong;Dang, Nana;Vanderkerken, Karin
髓样细胞白血病-1（Mcl-1）蛋白是一种抗凋亡Bcl-2家族蛋白，在多发性骨髓瘤（MM）的生存和耐药性中发挥重要作用。在MM中，已证明蛋白酶体抑制可触发Mcl-1的蓄积，这已显示赋予MM细胞对硼替佐米诱导的致死性的抗性。然而，这种不必要的Mcl-1积累所涉及的机制仍不清楚。本研究的目的是确定不需要的Mcl-1积累是否可以诱导的未折叠蛋白反应（UPR），并阐明内质网应激反应在调节Mcl-1表达的作用。利用定量RT-PCR和Western blot，我们发现，转录激活因子-4（ATF 4）的翻译，一个重要的效应的UPR，也大大提高了蛋白酶体抑制剂。ChIP分析进一步揭示硼替佐米刺激ATF 4与Mcl-1基因启动子上的调控位点（332 - 324位）结合。通过下调硼替佐米对Mcl-1的诱导作用来抑制ATF 4的敲低，并显著增加硼替佐米诱导的细胞凋亡。这些数据确定了UPR，更具体地说，其ATF 4分支是通过蛋白酶体抑制介导Mcl-1上调的重要机制。（血。2012;119（3）：826-837）
Myeloid cell leukemia-1 (Mcl-1) protein is an anti-apoptotic Bcl-2 family protein that plays essential roles in multiple myeloma (MM) survival and drug resistance. In MM, it has been demonstrated that proteasome inhibition can trigger the accumulation of Mcl-1, which has been shown to confer MM cell resistance to bortezomib-induced lethality. However, the mechanisms involved in this unwanted Mcl-1 accumulation are still unclear. The aim of the present study was to determine whether the unwanted Mcl-1 accumulation could be induced by the unfolded protein response (UPR) and to elucidate the role of the endoplasmic reticulum stress response in regulating Mcl-1 expression. Using quantitative RT-PCR and Western blot, we found that the translation of activating transcription factor-4 (ATF4), an important effector of the UPR, was also greatly enhanced by proteasome inhibition. ChIP analysis further revealed that bortezomib stimulated binding of ATF4 to a regulatory site (at position 332 to 324) at the promoter of the Mcl-1 gene. Knocking down ATF4 was paralleled by down-regulation of Mcl-1 induction by bortezomib and significantly increased bortezomib-induced apoptosis. These data identify the UPR and, more specifically, its ATF4 branch as an important mechanism mediating up-regulation of Mcl-1 by proteasome inhibition. (Blood. 2012;119(3):826-837)