Frantsve J, Schwaller J, Sternberg D W, Kutok J, Gilliland D G
Division of Hematology, Department of Medicine, Boston, Massachusetts 02115.
Mol Cell Biol. 2001 May;21(10):3547-57. doi: 10.1128/MCB.21.10.3547-3557.2001.
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.
TEL-JAK2融合蛋白是与人类白血病相关的t(9;12)(p24;p13)易位的产物，在体外和体内均可激活Stat5，并在小鼠骨髓移植模型中引起骨髓和淋巴细胞增殖性疾病。我们报告，Socs-1是JAK和STAT内源性抑制剂的SOCS家族成员，可抑制TEL-JAK2对Ba/F3细胞的转化，但对由BCR-ABL、TEL-ABL或TEL-血小板衍生生长因子受体β转化的Ba/F3细胞没有影响。TEL-JAK2除了激活Stat5外，还与Shc和Grb2结合并诱导Erk2激活，而Socs-1的表达抑制了这些信号分子中每一个的参与。通过体外激酶测定评估，Socs-1可抑制TEL-JAK2激酶活性。此外，Socs-1可诱导TEL-JAK2的蛋白酶体降解。突变分析表明，Socs-1的SOCS框是蛋白酶体降解和消除TEL-JAK2转化细胞生长所必需的。此外，小鼠骨髓移植试验表明，Socs-1的表达可延长体内TEL-JAK2介导疾病的潜伏期。这些数据共同表明，Socs-1在体外和体内均可通过抑制激酶活性和诱导TEL-JAK2蛋白降解来抑制TEL-JAK2。
