Positive interactions between STAP-1 and BCR-ABL influence chronic myeloid leukemia cell proliferation and survival
Positive interactions between STAP-1 and BCR-ABL influence chronic myeloid leukemia cell proliferation and survival
复制标题
DOI：
10.1016/j.bbrc.2021.03.162
复制
发表时间：
2021-04-09
影响因子：
3.1
通讯作者：
Matsuda, Tadashi
中科院分区：
文献类型：
--
作者：
Ishiura, Marie;Kitai, Yuichi;Matsuda, Tadashi
慢性髓性白血病（CML）是一种以费城染色体及其致癌产物BCR-ABL的存在为特征的克隆性疾病，BCR-ABL激活参与细胞存活、生长促进和疾病进展的多种途径。我们最近报道了信号转导接头蛋白1 （STAP-1）在CML干细胞（LSCs）中上调，并通过上调stat5下游抗凋亡基因来减少CML LSCs的凋亡。在这项研究中，我们详细展示了BCR-ABL、STAP-1和转录信号换能器和激活因子5 （STAT5）之间的分子相互作用。对缺失突变体的研究表明，STAP-1分别通过其SH2和PH结构域与BCR-ABL和STAT5a相互作用，提示STAP-1可能作为支架蛋白。此外，STAP-1与BCR-ABL的结合稳定了CML细胞中的BCR-ABL蛋白。由于STAP-1在CML细胞中高表达，我们还使用荧光素酶报告基因构建体分析了STAP-1启动子的活性，发现NFATc1参与激活STAP-1启动子并诱导STAP-1 mRNA的表达。我们的研究结果表明，STAP-1分别通过BCR-ABL/STAT5和BCR-ABL/Ca2+/NFAT信号诱导CML细胞增殖和STAP-1 mRNA表达。(C) 2021爱思唯尔公司版权所有。
Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia chromosome and its oncogenic product, BCR-ABL, which activates multiple pathways involved in cell survival, growth promotion, and disease progression. We recently reported that signal-transducing adaptor protein 1 (STAP-1) is upregulated in CML stem cells (LSCs) and functions to reduce the apoptosis of CML LSCs by upregulating the STAT5-downstream anti-apoptotic genes. In this study, we demonstrate the detailed molecular interactions among BCR-ABL, STAP-1, and signal transducer and activator of transcription 5 (STAT5). Studies with deletion mutants have revealed that STAP-1 interacts with BCR-ABL and STAT5a through its SH2 and PH domains, respectively, suggesting the possible role of STAP-1 as a scaffold protein. Furthermore, the binding of STAP-1 to BCR-ABL stabilizes the BCR-ABL protein in CML cells. Since STAP-1 is highly expressed in CML cells, we also analyzed the STAP-1 promoter activity using a luciferase reporter construct and found that NFATc1 is involved in activating the STAP-1 promoter and inducing STAP-1 mRNA expression. Our results demonstrate that STAP-1 contributes to the BCR-ABL/STAT5 and BCR-ABL/Ca2+/NFAT signals to induce proliferation and STAP-1 mRNA expression in CML cells, respectively. (C) 2021 Elsevier Inc. All rights reserved.