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首页> 外文期刊>Cellular Signalling >Phosphorylated CIS suppresses the Epo or JAK2 V617F mutant-triggered cell proliferation through binding to EpoR
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Phosphorylated CIS suppresses the Epo or JAK2 V617F mutant-triggered cell proliferation through binding to EpoR

机译：磷酸化的顺式抑制EPO或JAK2 V617F突变体触发的细胞增殖通过结合EPOR

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摘要

The JAK2 V617F mutant -mediated aberrant signaling pathway is a hallmark of myeloproliferative neoplasms (MPNs). Although cytokine-inducible Src homology 2 protein (CIS) and suppressors of cytokine signaling (SOCS) are negative regulators of the JAK-STAT pathway, the functional role of CIS/SOCS family members in the JAK2 V617F mutant -induced oncogenic signaling pathway has not yet been elucidated. In this study, we found that the expression of CIS and SOCS1 was induced through the activation of signal transducer and activator of transcription 5 (STAT5) in not only the cells stimulated with Epo or IL -3 but also the cells transformed by the JAK2 V617F mutant. Cell proliferation and tumor formation in nude mice induced by the JAK2 V617F mutant were significantly enhanced when the expression of CIS was silenced using an RNA interference technique, whereas the knockdown of SOCS1 had no effect. The enforced expression of CIS caused apoptotic cell death in the transformed by JAK2 V617F mutant and drastically inhibited the JAK2 V617F mutant -induced tumor formation. CIS interacted with phosphorylated EpoR at Y401, which was critical for the activation of STAT5 and ERK. Whereas the activation of STAT5 and ERK in the transformed cells by JAK2 V617F mutant was increased by the knockdown of CIS, the enforced expression of CIS reduced the activation of these molecules. Furthermore, these anti -tumor effects of CIS required the function of SH2 domain and its tyrosine phosphorylation at Y253. We herein elucidated the mechanism by which CIS functions as a novel type of tumor suppressor in JAK2 V617F mutant -induced tumorigenesis. (C) 2016 Elsevier Inc. All rights reserved.
机译：JAK2 V617F突变体介导的异常信号通路是骨髓增生性肿瘤（MPN）的标志。虽然细胞因子诱导的Src同源2蛋白（CIS）和细胞因子信号抑制因子（SOCS）是JAK-STAT通路的负调节因子，但CIS/SOCS家族成员在JAK2 V617F突变诱导的致癌信号通路中的功能作用尚未阐明。在这项研究中，我们发现CIS和SOCS1的表达不仅通过Epo或IL-3刺激的细胞，而且通过激活信号转导子和转录激活子5（STAT5）在JAK2 V617F突变体转化的细胞中诱导。当使用RNA干扰技术沉默顺式表达时，JAK2 V617F突变体诱导的裸鼠细胞增殖和肿瘤形成显著增强，而敲除SOCS1则没有影响。CIS的强制表达导致JAK2 V617F突变体转化的细胞凋亡，并显著抑制JAK2 V617F突变体诱导的肿瘤形成。顺式在Y401处与磷酸化EpoR相互作用，这对STAT5和ERK的激活至关重要。JAK2 V617F突变体转化细胞中STAT5和ERK的激活通过顺式敲除而增加，而顺式的强制表达降低了这些分子的激活。此外，顺式抗肿瘤作用需要SH2结构域的功能及其在Y253处的酪氨酸磷酸化。在此，我们阐明了CIS在JAK2 V617F突变诱导的肿瘤发生中作为一种新型肿瘤抑制因子发挥作用的机制。（C） 2016爱思唯尔公司版权所有。

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