Dok1 and SHIP Act as Negative Regulators of v-Abl-Induced Pre-B Cell Transformation, Proliferation and Ras/Erk Activation
Dok1 and SHIP Act as Negative Regulators of v-Abl-Induced Pre-B Cell Transformation, Proliferation and Ras/Erk Activation
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DOI：
10.4161/cc.4.2.1417
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发表时间：
2005-02
期刊：
影响因子：
4.3
通讯作者：
S. Oki;Andre Limnander;P. M. Yao;M. Niki;P. Pandolfi;P. Rothman
中科院分区：
文献类型：
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作者：
S. Oki;Andre Limnander;P. M. Yao;M. Niki;P. Pandolfi;P. Rothman
在小鼠骨髓细胞转化过程中，v-Abl酪氨酸激酶激活几种信号通路。由于含SH 2的肌醇5 ′-磷酸酶（SHIP）和酪氨酸激酶1下游（Dok 1）已被证明与Abl相互作用，因此研究了SHIP和Dok 1缺陷对v-Abl转化的影响。Dok 1或SHIP缺陷小鼠的骨髓细胞对v-Abl的转化更敏感。这些敲除小鼠的v-Abl转化的前B细胞显示Abl激酶依赖的过度增殖和对凋亡的中度抵抗。在SHIP（-/-）或Dok 1（-/-）v-Abl转化的细胞中观察到Ras、Raf-1和Erk的激活升高，但Akt没有。这种激活对STI 571治疗敏感。此外，用法尼基转移酶抑制剂或MEK 1/2抑制剂处理这些细胞以剂量依赖性方式消除SHIP（-/-）或Dok 1（-/-）细胞的增殖增加。补充SHIP（-/-）或Dok 1（-/-）细胞可消除其过度增殖和细胞内ERK激活。这些结果表明SHIP和Dok 1在功能上调节v-Abl对Ras-Erk通路的激活，并影响v-Abl转化的骨髓细胞的促有丝分裂活性。
The v-Abl tyrosine kinase activates several signaling pathways during transformation of bonemarrow cells in mice. Because the SH2-containing inositol 5’-phosphatase (SHIP) andDownstream of tyrosine kinase 1 (Dok1) have been shown interact with Abl, the effect ofSHIP and Dok1 deficiency on v-Abl transformation was investigated. Bone marrow cellsfrom either Dok1- or SHIP-deficient mice are more susceptible to transformation by v-Abl.v-Abl-transformed pre-B cells from these knockout mice show Abl kinase-dependenthyperproliferation 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-transformedcells. This activation is sensitive to treatment with STI571. Furthermore, treatment of thesecells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increasedproliferation of SHIP (-/-) or Dok1 (-/-) cells in a dose-dependent manner. Complementationof SHIP (-/-) or Dok1 (-/-) cells abrogates their hyperproliferation and intracellular Erkactivation. These data indicate that both SHIP and Dok1 functionally regulate the activationof Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bonemarrow cells.