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首页> 外文期刊>Molecular and Cellular Biology >Socs-1 Inhibits TEL-JAK2-Mediated Transformation of Hematopoietic Cells through Inhibition of JAK2 Kinase Activity and Induction of Proteasome-Mediated Degradation
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Socs-1 Inhibits TEL-JAK2-Mediated Transformation of Hematopoietic Cells through Inhibition of JAK2 Kinase Activity and Induction of Proteasome-Mediated Degradation

机译：Socs-1通过抑制JAK2激酶活性和诱导蛋白酶体介导的降解来抑制TEL-JAK2介导的造血细胞转化。

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TEL-JAK2 fusion proteins, which are a result of t(9;12)(p24;p13) translocations associated with human leukemia, activate Stat5 in vitro and in vivo and cause a myelo- and lymphoproliferative disease in a murine bone marrow transplant model. We report that Socs-1, a member of the SOCS family of endogenous inhibitors of JAKs and STATs, inhibits transformation of Ba/F3 cells by TEL-JAK2 but has no effect on Ba/F3 cells transformed by BCR-ABL, TEL-ABL, or TEL–platelet-derived growth factor receptor beta. TEL-JAK2, in addition to activating Stat5, associates with Shc and Grb2 and induces activation of Erk2, and expression of Socs-1 inhibits engagement of each of these signaling molecules. TEL-JAK2 kinase activity is inhibited by Socs-1, as assessed by in vitro kinase assays. In addition, Socs-1 induces proteasomal degradation of TEL-JAK2. Mutational analysis indicates that the SOCS box of Socs-1 is required for proteasomal degradation and for abrogation of growth of TEL-JAK2-transformed cells. Furthermore, murine bone marrow transplant assays demonstrate that expression of Socs-1 prolongs latency of TEL-JAK2-mediated disease in vivo. Collectively, these data indicate that Socs-1 inhibits TEL-JAK2 in vitro and in vivo through inhibition of kinase activity and induction of TEL-JAK2 protein degradation.
机译：TEL-JAK2融合蛋白是与人类白血病相关的t（9; 12）（p24; p13）易位的结果，可在体内和体外激活Stat5，并在小鼠骨髓移植模型中引起骨髓增生和淋巴增生性疾病。我们报告说Socs-1，JAKs和STATs的内源性抑制剂的SOCS家族成员，抑制TEL-JAK2对Ba / F3细胞的转化，但对BCR-ABL，TEL-ABL转化的Ba / F3细胞没有影响，或TEL血小板衍生的生长因子受体β。 TEL-JAK2除了激活Stat5外，还与Shc和Grb2缔合并诱导Erk2激活，而Socs-1的表达抑制这些信号分子中的每一个的参与。通过体外激酶测定评估，SOCS-1抑制了TEL-JAK2激酶的活性。另外，Socs-1诱导TEL-JAK2的蛋白酶体降解。突变分析表明，SOCS-1的SOCS盒对于蛋白酶体降解和TEL-JAK2转化细胞的生长废止是必需的。此外，鼠类骨髓移植试验证明，SOCS-1的表达延长了TEL-JAK2介导的疾病在体内的潜伏期。总的来说，这些数据表明，Socs-1通过抑制激酶活性和诱导TEL-JAK2蛋白降解而在体外和体内抑制TEL-JAK2。

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