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首页> 外文期刊>Cell cycle >Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation.
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Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation.

机译：Dok1和SHIP充当v-Abl诱导的B前细胞转化，增殖和Ras / Erk激活的负调节剂。

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The v-Abl tyrosine kinase activates several signaling pathways during transformation of bone marrow cells in mice. Because the SH2-containing inositol 5'-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated. Bone marrow cells from either Dok1- or SHIP-deficient mice are more susceptible to transformation by v-Abl. v-Abl-transformed preB cells from these knockout mice show Abl kinase-dependent hyperproliferation and moderate resistance to apoptosis. Elevated activation of Ras, Raf-1, and Erk, but not of Akt, was observed in either SHIP(-/-) or Dok1(-/-) v-Abl-transformed cells. This activation is sensitive to treatment with STI571. Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP(-/-) or Dok1(-/-) cells in a dose-dependent manner. Complementation of SHIP(-/-) or Dok1(-/-) cells abrogates their hyperproliferation and intracellular Erk activation. These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells.
机译：在小鼠骨髓细胞转化过程中，v-Abl酪氨酸激酶激活了多个信号通路。因为已显示含SH2的肌醇5'-磷酸酶（SHIP）和酪氨酸激酶1下游（Dok1）与Abl相互作用，所以研究了SHIP和Dok1缺乏对v-Abl转化的影响。来自Dok1或SHIP缺陷小鼠的骨髓细胞更易受v-Abl转化。来自这些基因敲除小鼠的v-Abl转化的preB细胞显示出Abl激酶依赖性过度增殖和对凋亡的中等抵抗力。在SHIP（-/-）或Dok1（-/-）v-Abl转化细胞中观察到Ras，Raf-1和Erk的活化增强，但Akt却没有。此激活对STI571的治疗敏感。此外，用法呢基转移酶抑制剂或MEK1 / 2抑制剂处理这些细胞以剂量依赖的方式消除了SHIP（-/-）或Dok1（-/-）细胞增殖的增加。 SHIP（-/-）或Dok1（-/-）细胞的互补消除了它们的过度增殖和细胞内Erk激活。这些数据表明，SHIP和Dok1都在功能上调节v-Abl激活Ras-Erk途径并影响v-Abl转化的骨髓细胞的促有丝分裂活性。

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