The anti-apoptotic role of the unfolded protein response in Bcr-Abl-positive leukemia cells
The anti-apoptotic role of the unfolded protein response in Bcr-Abl-positive leukemia cells
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DOI：
10.1016/j.leukres.2009.01.027
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发表时间：
2009-07-01
影响因子：
2.7
通讯作者：
Tanizawa, Yukio
中科院分区：
文献类型：
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作者：
Tanimura, Atsuko;Yujiri, Toshiaki;Tanizawa, Yukio
为了确定未折叠蛋白反应（UPR）在白血病发生中的作用，我们研究了表达代表性癌基因Bcr-Abl（B-A）的细胞中UPR的激活。B-A组中UPR相关蛋白和mRNA的表达增加，即X-box-binding protein（XBP 1）和glucose-regulated protein 78（GRP 78）。使用肌醇需要酶1 α（IRE 1 α）或激活转录因子6（ATF 6）显性阴性突变体抑制UPR，降低了Bcr-Abl保护细胞免受依托泊苷和伊马替尼诱导的凋亡的能力。我们还发现，UPR相关基因在Ph阳性白血病原代细胞中的表达明显高于对照组，提示UPR是Bcr-Abl的下游靶基因，在Ph阳性白血病细胞中起抗凋亡作用。(C)2009爱思唯尔有限公司保留所有权利。
To define the role of the unfolded protein response (UPR) in leukemogenesis, we investigated UPR activation in the cells expressing the representative oncogene Bcr-Abl (B-A). The expression of UPR-related proteins and mRNAs, namely, X-box-binding protein (XBP1) and glucose-regulated protein 78 (GRP78) was increased in B-A. UPR inhibition using inositol-requiring enzyme 1 alpha (IRE1 alpha) or activating transcription factor 6 (ATF6) dominant-negative mutants diminished the ability of Bcr-Abl to protect the cells from etoposide- and imatinib-induced apoptosis. We also noted that the expression of UPR-related genes in primary leukemia cells from Philadelphia chromosome (Ph)-positive cells was higher than that in the control by quantitative RT-PCR assay Thus, our results suggested that UPR is a downstream target of Bcr-Abl and plays an anti-apoptotic role in Ph-positive leukemia cells. (C) 2009 Elsevier Ltd. All rights reserved.