Analysis of molecular mechanisms of leukemia development

Evi-1编码一种锌指蛋白，参与造血细胞的白血病转化。Evi-1是一个由7个和3个重复的锌指基序组成的两个结构域，其转录调控特性已被描述。虽然Evi-1被认为具有促进某些类型细胞生长或阻断其分化的能力，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是否干扰转化生长因子β（TGFβ）的信号传导，TGF β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抑制TGFβ信号传导并拮抗TGFβ的生长抑制作用。Evi-1的两个独立区域负责这种抑制，其中之一是第一锌指结构域。通过该结构域，Evi-1与Smad 3（TGFβ信号传导的细胞内介质）物理相互作用，从而抑制Smad 3的转录活性。这些结果定义了Evi-1作为TGFβ信号传导组分的阻遏物的新功能。我们还发现Evi-1作为cJun N-末端激酶（JNK）的抑制剂，JNK也称为应激活化蛋白激酶（SAPK），其是一类与细胞凋亡、免疫应答和造血细胞因子的信号传导途径有关的促分裂原活化蛋白（MAP）激酶。Evi-1与JNK/SAPK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的新的生化和生物活性，其提供了核癌基因产物抑制JNK/SAPK的证据。在MAP激酶中，Evi-1选择性地抑制JNK/SAPK，从而阻断由细胞应激诱导的凋亡性细胞死亡，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.