Role of Dok-1 and Dok-2 in leukemia suppression.
Role of Dok-1 and Dok-2 in leukemia suppression.
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DOI：
10.1084/jem.20041306
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发表时间：
2004-12-20
影响因子：
15.3
通讯作者：
Pandolfi, PP
中科院分区：
文献类型：
--
作者：
Niki, M;Di Cristofano, A;Zhao, MM;Honda, H;Hirai, H;Van Aelst, L;Cordon-Cardo, C;Pandolfi, PP
慢性粒细胞白血病（CML）的特征是存在嵌合p210 bcr/abl癌蛋白，其相对于正常c-abl酪氨酸激酶显示出升高的组成性蛋白酪氨酸激酶活性。虽然已经鉴定了几种p210 bcr/abl底物，但其在疾病发病机制中的相关性尚不清楚。我们已经鉴定出在造血祖细胞中共表达的蛋白质家族Dok（酪氨酸激酶下游）。该家族的成员如p62 dok（Dok-1）和p56 dok-2（Dok-2）在被p210 bcr/abl以及受体和非受体酪氨酸激酶磷酸化后与p120 rasGTP酶激活蛋白（rasGAP）结合。在这里，我们报告单和双Dok-1或Dok-2敲除（KO）突变体的产生和表征。单KO小鼠显示正常稳态造血。相反，伴随的Dok-1和Dok-2失活导致异常造血和Ras/MAP激酶激活。引人注目的是，所有Dok-1/Dok-2双KO突变体由于细胞增殖增加和细胞凋亡减少而自发地发展为可移植CML样骨髓增生性疾病。此外，Dok-1或Dok-2失活显著加速Tec-p210 bcr/abl转基因小鼠的白血病和急变期发作，已知该小鼠在长潜伏期后发生类似于人CML的骨髓增生性疾病。这些发现揭示了Dok-1和Dok-2在肿瘤抑制和造血区室稳态控制中的关键和意想不到的作用。
Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok(Dok-1) and p56dok-2(Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210 bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.
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影响因子：
20.3
作者：
Honda, H;Ushijima, T;Hirai, H
通讯作者：
Hirai, H
影响因子：
20.3
作者：
Honda, H;Oda, H;Hirai, H
通讯作者：
Hirai, H
影响因子：
64.5
作者：
Yamanashi, Y;Baltimore, D
通讯作者：
Baltimore, D
影响因子：
56.9
作者：
Di Cristofano, A;Kotsi, P;Pandolfi, PP
通讯作者：
Pandolfi, PP
影响因子：
11.4
作者：
Suzu, S;Tanaka-Douzono, M;Motoyoshi, K
通讯作者：
Motoyoshi, K