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首页> 外文学位 >Characterization of the transformation and signal transduction properties of TEL/JAK2 fusion proteins associated with human leukemias.
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Characterization of the transformation and signal transduction properties of TEL/JAK2 fusion proteins associated with human leukemias.

机译：TEL / JAK2融合蛋白与人类白血病相关的转化和信号转导特性的表征。

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摘要

Three TEL/JAK2 fusion variants that are the consequence of t(9;12)(p24;p13) chromosomal translocations have been identified in patients with T-cell acute lymphoblastic leukemia, preB-cell acute lymphoblastic leukemia, and atypical chronic myelogenous leukemia. The translocations result in the fusion of the pointed domain (PNT) of TEL, which mediates oligomerization of the protein, to the JH1 kinase domain of JAK2. All fusion variants transform the murine hematopoietic cell line, Ba/F3, to factor independent growth and cause a myelo- and lymphoproliferative disease in a murine bone marrow transplant model. Mutational analysis has demonstrated that transformation of hematopoietic cells by TEL/JAK2 in vitro and in vivo requires the PNT domain of TEL as well as the kinase activity of the JAK2 JH1 domain. TEL/JAK2 activates STAT5, members of the RAS/MAP kinase pathway, members of the PI3K/AKT pathway, and engages the Gab2 adaptor protein. TEL/JAK2 murine bone marrow transplants conducted in a Stat5a/b deficient background indicate that Stat5 is essential for the TEL/JAK2-mediated disease, and transplants conducted in a Gab2 deficient background indicate that loss of this adaptor protein attenuates the myeloproliferative phenotype induced by TEL/JAK2. Expression of Socs-1, a member of the SOCS family of endogenous inhibitors of JAKs and STATs, inhibits engagement of each of these signaling pathways through two distinct mechanisms: inhibition of TEL/JAK2 kinase activity and proteasomal-mediated degradation of the fusion protein. Furthermore, Socs1 expression specifically inhibits in vitro and in vivo transformation by TEL/JAK2. Tyrosine phosphorylation of Socs1 by TEL/JAK2 regulates its ability to impair TEL/JAK2 transformation. These data demonstrate that TEL/JAK2 transforms hematopoietic cell lines and primary hematopoietic progenitor cells through activation of STAT5, the RAS/MAP kinase pathway and the PI3K/AKT pathway, and that expression of Socs1 can inhibit transformation. This research has further elucidated our understanding of the mechanism by which constitutively activated tyrosine kinases transform cells in human cancers.
机译：在患有T细胞急性淋巴细胞白血病，B细胞前急性淋巴细胞白血病和非典型慢性粒细胞白血病的患者中，已鉴定出t（9; 12）（p24; p13）染色体易位的三种TEL / JAK2融合变体。易位导致介导蛋白质寡聚化的TEL的指向结构域（PNT）与JAK2的JH1激酶结构域融合。所有融合变体均可转化鼠造血细胞系Ba / F3，使其独立生长并在鼠骨髓移植模型中引起骨髓增生和淋巴增生性疾病。突变分析表明，体外通过TEL / JAK2和体内通过ITA / JAK2转化造血细胞需要TEL的PNT结构域以及JAK2 JH1结构域的激酶活性。 TEL / JAK2激活STAT5，RAS / MAP激酶途径的成员，PI3K / AKT途径的成员，并激活Gab2衔接子蛋白。在Stat5a / b缺乏背景下进行的TEL / JAK2鼠骨髓移植表明Stat5对于TEL / JAK2介导的疾病至关重要，在Gab2缺乏背景下进行的移植表明该衔接子蛋白的缺失减弱了由ATP诱导的骨髓增殖表型TEL / JAK2。 Socs-1（JAK和STATs的内源性抑制剂的SOCS家族的成员）的表达通过两种不同的机制抑制这些信号传导途径的参与：抑制TEL / JAK2激酶活性和蛋白酶体介导的融合蛋白降解。此外，Socs1表达通过TEL / JAK2特异性抑制体外和体内转化。 TEL / JAK2对Socs1的酪氨酸磷酸化调节其削弱TEL / JAK2转化的能力。这些数据表明，TEL / JAK2通过激活STAT5，RAS / MAP激酶途径和PI3K / AKT途径来转化造血细胞系和原代造血祖细胞，而Socs1的表达可以抑制转化。这项研究进一步阐明了我们对组成型激活的酪氨酸激酶转化人类癌症细胞的机制的理解。

著录项

  • 作者

    Frantsve, Julie Carolyn.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Health Sciences Oncology.; Biology Genetics.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 264 p.
  • 总页数 264
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;遗传学;分子遗传学;
  • 关键词

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