Analysis of molecular mechanisms of leukemia development

白血病发生发展的分子机制分析

基本信息

批准号：
09307021
负责人：
HIRAI Hisamaru
金额：
$ 24.58万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Evi-1 encodes a zinc finger protein implicated in leukemic transform ation of hematopoietic cells. Evi-1 posses seven and three repeats of zinc finger motifs separated into two domains, and characteristics as a transcriptional regulator have been described. Although Evi-1 is thought to possess the abilities to promote growth or to block differentiation in some types of cell, its biological functions have been poorly understood. To explore mechanisms that underlie oncogenesis induced by Evi-1, we investigated whether Evi-1 perturbs signalling of transforming growth factor β (TGFβ), one of the most studied growth regulatory factors that inhibit proliferatic of a wide range of cell types. We demonstrated that Evi-1 represses TGFβ signalling and antagonizes growth-inhibitory effects of TGFβ. Two separate regions of Evi-1 are responsible for this repression, one of which is tl first zinc finger domain. Through this domain, Evi-1 physically interacts with Smad3, an intracellular mediato TGFβ signalling, thereby suppressing the transcriptional activity of Smad3. These results define a novel functi of Evi-1 as a repressor of signalling components of TGFβ. We also showed that Evi-1 acts as an inhibitor of c Jun N-terminal kinase (JNK), also called stress-activated protein kinase (SAPK), a class of mitogen-activated protein (MAP) kinasess which is implicated in apoptosis, the immuneresponse and signalling pathway of hematopoietic cytokines. Evi-1 physically interacts with JNK/SAPK and protects cells from ultraviolet (UV)- induced cell death. This reveals a novel biochemical and biological activity of Evi-1, which provides an evider for inhibition of JNK/SAPK by a nuclear oncogene product. Among MAP kinases, Evi-1 selectively inhibits JNK/SAPK and thus blocks apoptotic cell death induced by cellular stresses, thereby contributing to oncogenic transformation of cells.

Evi-1 编码与造血细胞的白血病转化有关的锌指蛋白，Evi-1 具有分成两个结构域的七个和三个重复的锌指基序，并且已经描述了 Evi-1 作为转录调节因子的特征。尽管 Evi-1 具有促进生长或阻止某些类型细胞分化的能力，但其生物学功能却知之甚少。为了探索 Evi-1 诱导肿瘤发生的机制，我们研究了 Evi-1 是否存在。干扰转化生长因子 β (TGFβ) 的信号传导，TGFβ 是研究最多的生长调节因子之一，可抑制多种细胞类型的增殖。我们证明，Evi-1 可以抑制 TGFβ 信号传导并拮抗 TGFβ 的两种不同的生长抑制作用。 Evi-1 的区域负责这种抑制，其中一个是第一个锌指结构域，Evi-1 通过该结构域与细胞内介质 Smad3 发生物理相互作用。 TGFβ 信号传导，抑制 Smad3 的转录活性。因此，这些结果定义了 Evi-1 作为 TGFβ 信号传导成分的阻遏物。我们还表明，Evi-1 作为 c Jun N 末端激酶 (JNK) 的抑制剂。），也称为应激激活蛋白激酶（SAPK），一类丝裂原激活蛋白（MAP）激酶，与细胞凋亡、免疫反应和信号通路有关。 Evi-1 与 JNK/SAPK 发生物理相互作用，并保护细胞免受紫外线 (UV) 诱导的细胞死亡，这揭示了 Evi-1 的新生化和生物活性，为抑制 JNK/SAPK 提供了证据。在 MAP 激酶中，Evi-1 选择性抑制 JNK/SAPK，从而阻止细胞应激诱导的细胞凋亡，从而促进细胞的致癌转化。