Analysis of molecular mechanisms of leukemia development

Evi-1编码一种锌指蛋白，与造血细胞的白血病转化有关。Evi-1具有7个和3个重复的锌指基序，分为两个结构域，作为转录调控因子的特征已被描述。尽管Evi-1被认为在某些类型的细胞中具有促进生长或阻止分化的能力，但其生物学功能一直知之甚少。为了探索Evi-1诱导肿瘤发生的机制，我们研究了Evi-1是否干扰转化生长因子β(转化生长因子β)的信号传递，转化生长因子是研究最多的生长调节因子之一，可以抑制多种细胞类型的增殖。我们证明，Evi-1抑制转化生长因子β信号转导，拮抗转化生长因子β的生长抑制作用。Evi-1的两个独立区域负责这种抑制，其中一个区域是Tl第一锌指结构域。通过这个结构域，Evi-1与Smad3发生物理作用，Smad3是细胞内介导转化生长因子β信号的媒介，从而抑制Smad3的转录活性。这些结果确定了Evi-1的一个新功能，即作为转化生长因子β的信号成分的抑制因子。我们还发现，Evi-1是c-jun氨基末端激酶(JNK)的抑制因子，也称为应激激活蛋白激酶(SAPK)，是一种丝裂原活化蛋白(MAP)，与细胞凋亡、造血细胞因子的免疫反应和信号通路有关。Evi-1在物理上与JNK/SAPK相互作用，保护细胞免受紫外线(UV)诱导的细胞死亡。这揭示了Evi-1新的生化和生物学活性，为核癌基因产物抑制JNK/SAPK提供了证据。在MAP激酶中，Evi-1选择性地抑制JNK/SAPK，从而阻断细胞应激诱导的细胞死亡，从而促进细胞的致癌转化。

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.