Suppressopm of growth of leukemia cells by a tyrosine kinase inhibitor JAB

在人类白血病中发现12 p13的TEL基因与9 p24的JAK 2酪氨酸激酶基因融合。TEL介导的JAK 2寡聚化导致酪氨酸激酶（JH 1）结构域的组成性激活，并赋予白细胞介素-3依赖性Ba/F3细胞非依赖性增殖。JAK抑制基因SOCS 1/JAB/SSI-1的强制表达诱导TEL-JAK 2转化的Ba/F3细胞凋亡。TEL-JAK 2活性的这种抑制依赖于SOCS盒介导的TEL-JAK 2蛋白酶体降解，而不是激酶抑制。JAK 2的降解依赖于其磷酸化及其通过激酶抑制区和SH 2结构域与SOCS 1的高亲和力结合。VHL抑癌基因产物具有与Elongin B、C和Cullin-2形成复合物的SOCS盒，具有泛素连接酶的功能，SOCS盒1也与Elongins相互作用，但其泛素连接酶活性尚未被证实。我们发现SOCS box与Cullin 2相互作用，促进TEL-JAK 2的泛素化。此外，显性负性Cullin 2的过表达抑制SOCS 1依赖的TEL-JAK 2降解。我们的研究表明SOCS 1对激活的JAK 2具有底物特异性的E3泛素连接酶样活性，并可能为抑制致癌酪氨酸激酶提供一种新的策略。

Fusion of the TEL gene on 12p13 to the JAK2 tyrosine kinase gene on 9p24 has been found in human leukemia. TEL-mediated oligomerization of JAK2 results in constitutive activation of the tyrosine kinase (JH1) domain and confers cytokine-independent proliferation to interleukin-3-dependent Ba/F3 cells. Forced expression of the JAK inhibitor gene SOCS1/JAB/SSI-1 induced apoptosis of TEL-JAK2-transformed Ba/F3 cells. This suppression of TEL-JAK2 activity was dependent on SOCS box-mediated proteasomal degradation of TEL-JAK2 rather than on kinase inhibition. Degradation of JAK2 depended on its phosphorylation and its high affinity binding with SOCS1 through the kinase inhibitory region and the SH2 domain. It has been demonstrated that von Hippel-Lindau disease (VHL) tumor-suppressor gene product possesses the SOCS box that forms a complex with Elongin B, C and Cullin-2, and functions as an ubiquitin ligase.The SOCS box of SOCS1 has also been shown to interact with Elongins, however, ubiquitin ligase activity has not been demonstrated. We found that the SOCS box interacted with Cullin2 and promoted ubiquitination of TEL-JAK2.Furthermore, overexpression of dominant negative Cullin 2 suppressed SOCS1-dependent TEL-JAK2 degradation. Our study demonstrates substrate-specific E3 ubiquitin-ligase like activity of SOCS1 for activated JAK2, and may provide a novel strategy for the suppression of oncogenic tyrosine kinases.