权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Analysis of unfolded protein response in hematological malignancy

血液恶性肿瘤中未折叠蛋白反应的分析

基本信息

批准号：
18591066
负责人：
YUJIRI Toshiaki
金额：
$ 2.52万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591066/
关键词：
Unfolded protein response Leukemia Bet-Abl Apoptosis 癌シグナル伝達内科

项目摘要

The unfolded protein response (UPR) is activated in various tumors and may play a crucial role in tumor growth. However, the role of the UPR in leukemia remains unclear. Therefore, to define the role of the UPR in leukemogenesis, we investigated UPR activation in a cell line expressing the representative oncogene Bcr-Abl (B-A). The expression of UPR-related proteins, namely, X-box-binding protein (XBP1) and glucose-regulated protein 78 (GRP78), and of phosphorylated eukaryotic translation initiation factor 2α (eIF2α) was increased in B-A. Using a luciferase assay, we observed that Bcr-Abl induced high levels of the transcriptional activity of the cis-acting UPR element. Moreover, the mRNA levels of the UPR-related genes, namely, spliced form of XBPI; GRP78; and p58IPK, a cellular inhibitor of the RNA-dependent protein kinase, increased in B-A. UPR inhibition using inositol-requiring enzyme lα (IRE1α) 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; however, it had no effect on the proliferation of Bcr-Abl-transformed cells. 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 reverse transcription-polymerase chain reaction assay. Thus, our results suggested that UPR is a downstream target of Bcr-Abl and plays an anti-apoptotic role of Bcr-Abl in Ph-positive leukemia cells.

未折叠蛋白反应（UPR）在各种肿瘤中被激活，并可能在肿瘤生长中起关键作用。然而，UPR在白血病中的作用仍不清楚。因此，为了确定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）的细胞系中UPR的激活。在B-A中，UPR相关蛋白，即X-box-binding protein（XBP 1）和葡萄糖调节蛋白78（GRP 78）以及磷酸化的真核翻译起始因子2α（eIF 2 α）的表达增加。使用荧光素酶测定，我们观察到，Bcr-Abl诱导高水平的转录活性的顺式作用UPR元件。此外，在B-A中，UPR相关基因的mRNA水平增加，即XBPI的剪接形式; GRP 78;和p58 IPK，RNA依赖性蛋白激酶的细胞抑制剂。使用肌醇需要酶1 α（IRE 1 α）或转录激活因子6（ATF 6）显性阴性突变体抑制UPR可降低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;但对Bcr-Abl转化细胞的增殖无影响。我们还注意到，UPR相关基因的表达在原代白血病细胞从费城染色体（Ph）阳性细胞高于对照组通过定量逆转录-聚合酶链反应检测。因此，我们的研究结果表明，UPR是Bcr-Abl的下游靶点，并在Ph阳性白血病细胞中发挥Bcr-Abl的抗凋亡作用。