Growth arrest specific 2 is up-regulated in chronic myeloid leukemia cells and required for their growth.
Growth arrest specific 2 is up-regulated in chronic myeloid leukemia cells and required for their growth.
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生长停滞特异性 2 在慢性粒细胞白血病细胞中表达上调，并且是其生长所必需的
DOI：
10.1371/journal.pone.0086195
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zhou H;Ge Y;Sun L;Ma W;Wu J;Zhang X;Hu X;Eaves CJ;Wu D;Zhao Y
尽管BCR-ABL的产生是慢性粒细胞白血病（CML）的分子标志，但该疾病的全面分子机制仍不清楚。生长停滞特异性 2 (GAS2) 调节多种细胞功能，包括细胞周期、细胞凋亡和钙蛋白酶活性。在本研究中，我们发现与正常细胞相比，GAS2 在包括 CD34+ 祖细胞在内的 CML 细胞中表达上调。我们利用 RNAi 和 GAS2 显性失活形式 (GAS2DN) 的表达来靶向 GAS2，从而导致 K562 和 MEG-01 细胞钙蛋白酶活性增强并抑制生长。靶向 GAS2 还使 K562 细胞对甲磺酸伊马替尼 (IM) 敏感。 GAS2DN 抑制 MEG-01 细胞的致瘤能力并损害肿瘤生长。此外，用对照和 GAS2DN 慢病毒载体转导来自 CML 患者和健康供体的 CD34+ 细胞，并将 CD34+ 转导的 (YFP+) 子代细胞 (CD34+YFP+) 铺板进行集落形成细胞 (CFC) 测定。结果显示，GAS2DN抑制CML细胞CFC产生57±3%（n = 3），而影响正常造血细胞31±1%（n = 2）。接下来，我们发现 GAS2DN 对 CML 细胞的抑制依赖于钙蛋白酶活性，而不是 β-catenin 的降解。最后，我们生成了微阵列数据来识别 GAS2DN 上的差异表达基因，并验证了 HNRPDL、PTK7 和 UCHL5 的表达被 GAS2DN 抑制。与正常对照细胞相比，这 3 个基因在 CML 细胞中上调，并且 HNRPDL 沉默后 K562 细胞的生长受到抑制。综上所述，我们证明 GAS2 在 CML 细胞中上调，抑制 GAS2 会损害 CML 细胞的生长，这表明 GAS2 是 CML 细胞的新型调节因子，也是该疾病的潜在治疗靶点。
Although the generation of BCR-ABL is the molecular hallmark of chronic myeloid leukemia (CML), the comprehensive molecular mechanisms of the disease remain unclear yet. Growth arrest specific 2 (GAS2) regulates multiple cellular functions including cell cycle, apoptosis and calpain activities. In the present study, we found GAS2 was up-regulated in CML cells including CD34+ progenitor cells compared to their normal counterparts. We utilized RNAi and the expression of dominant negative form of GAS2 (GAS2DN) to target GAS2, which resulted in calpain activity enhancement and growth inhibition of both K562 and MEG-01 cells. Targeting GAS2 also sensitized K562 cells to Imatinib mesylate (IM). GAS2DN suppressed the tumorigenic ability of MEG-01 cells and impaired the tumour growth as well. Moreover, the CD34+ cells from CML patients and healthy donors were transduced with control and GAS2DN lentiviral vectors, and the CD34+ transduced (YFP+) progeny cells (CD34+YFP+) were plated for colony-forming cell (CFC) assay. The results showed that GAS2DN inhibited the CFC production of CML cells by 57±3% (n = 3), while affected those of normal hematopoietic cells by 31±1% (n = 2). Next, we found the inhibition of CML cells by GAS2DN was dependent on calpain activity but not the degradation of beta-catenin. Lastly, we generated microarray data to identify the differentially expressed genes upon GAS2DN and validated that the expression of HNRPDL, PTK7 and UCHL5 was suppressed by GAS2DN. These 3 genes were up-regulated in CML cells compared to normal control cells and the growth of K562 cells was inhibited upon HNRPDL silence. Taken together, we have demonstrated that GAS2 is up-regulated in CML cells and the inhibition of GAS2 impairs the growth of CML cells, which indicates GAS2 is a novel regulator of CML cells and a potential therapeutic target of this disease.
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影响因子：
158.5
作者：
Jamieson, CHM;Ailles, LE;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
5.3
作者：
Iervolino, A;Santilli, G;Perrotti, D
通讯作者：
Perrotti, D
GAS2是一种生长逮捕特异性蛋白，是微丝网络系统的组成部分。
影响因子：
7.8
作者：
Brancolini, C;Bottega, S;Schneider, C
通讯作者：
Schneider, C
在NIH 3T3细胞中，在GO中 - > G1过渡期间，生长阻塞特异性蛋白质GAS2的磷酸化与肌动蛋白重排耦合。
影响因子：
7.8
作者：
Brancolini, C;Schneider, C
通讯作者：
Schneider, C
影响因子：
11.4
作者：
Janssen, JJWM;Klaver, SM;Ossenkoppele, GJ
通讯作者：
Ossenkoppele, GJ