Tanimura Atsuko, Yujiri Toshiaki, Tanaka Yoshinori, Hatanaka Masayuki, Mitani Noriyuki, Nakamura Yukinori, Mori Kazutoshi, Tanizawa Yukio
Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Leuk Res. 2009 Jul;33(7):924-8. doi: 10.1016/j.leukres.2009.01.027. Epub 2009 Feb 23.
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 1alpha (IRE1alpha) 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.
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的激活情况。B-A中未折叠蛋白反应相关蛋白和mRNA，即X盒结合蛋白（XBP1）和葡萄糖调节蛋白78（GRP78）的表达增加。使用肌醇需求酶1α（IRE1α）或激活转录因子6（ATF6）显性负性突变体抑制UPR，会减弱Bcr-Abl保护细胞免受依托泊苷和伊马替尼诱导的细胞凋亡的能力。我们还通过定量逆转录聚合酶链反应（RT-PCR）检测发现，费城染色体（Ph）阳性原发性白血病细胞中未折叠蛋白反应相关基因的表达高于对照组。因此，我们的结果表明，UPR是Bcr-Abl的下游靶点，在Ph阳性白血病细胞中发挥抗凋亡作用。
