BCR-ABL TARGET IDENTIFICATION IN THE LEUKEMOGENIC PATHWA

描述：（改编自研究者摘要） 目的是阐明bcr-abl基因表达的分子机制， 癌基因在慢性粒细胞白血病（CML）的发病机制中起作用。 bcr-abl癌基因由染色体易位产生， 融合了断裂点簇区（bcr）基因的一部分和大部分 abl基因。该项目的重点是Bcr-Abl的相互作用， 其他蛋白质。Bcr-Abl中Abl酪氨酸激酶活性是必需的 肿瘤转化，表明Abl诱导白血病 通过靶蛋白的磷酸化。任博士的初步数据 表明Abl通过蛋白-蛋白募集特异性底物 由其非催化结构域介导的相互作用。任博士已经证明 Bcr-Abl和ABP结合蛋白Grb 2的共表达， 诱导小鼠CML样疾病。因此，他假设， ABPs在调节和介导肿瘤发生、发展中起重要作用。 在这个项目中，他将进一步确定ABP， 白血病细胞，并研究蛋白质-蛋白质 Bcr-Abl的致癌功能的相互作用。 目的是确定Bcr-Abl的致癌功能是否 是由其结合蛋白调节和/或介导的，如果是， Bcr-Abl的恶性潜能可以通过控制这些 交互.这些信息将有助于阐明致白血病的 Bcr-Abl激活的通路，并帮助开发治疗药物， 人类白血病因此，该项目的具体目标如下： 以下：（1）为了检验Grb 2或 Bcr-Abl的转化需要其他具有Bcr-Abl的ABP 通过检测Bcr-Abl中中断ABP的突变的影响， 结合肿瘤转化;（2）为了检验假设， 来源于CML患者的造血谱系细胞含有 通过识别Bcr-Abl的潜在靶点， CML细胞;（3）验证CML细胞的恶性潜能 Bcr-Abl可以通过中断Bcr-Abl之间的相互作用来减轻。 通过检查ABPs的过表达能力， 它们的突变多肽来阻止细胞转化。

DESCRIPTION: (adapted from the investigator's abstract) The broad objective is to elucidate the molecular mechanism by which the bcr-abl oncogene acts in the pathogenesis of chronic myelogenous leukemia (CML). The bcr-abl oncogene is created by a chromosomal translocation, which fuses a portion of the breakpoint cluster region (bcr) gene and most of the abl gene. The project focuses on the interaction of Bcr-Abl with other proteins. The Abl tyrosine kinase activity in Bcr-Abl is required for the neoplastic transformation, indicating that Abl induces leukemia through phosphorylation of target proteins. Dr. Ren's preliminary data indicate that Abl recruits specific substrates via protein-protein interactions mediated by its non-catalytic domains. Dr. Ren has shown that coexpression of Bcr-Abl and the Abl-binding protein (ABP) Grb2 induces a CML-like disease in mice. Therefore, he hypothesizes that the ABPs play important roles in regulating and mediating the oncogenic functions of Abl. In this project, he will further identify ABPs from the leukemic cells, and investigate the effect of the protein-protein interactions on the oncogenic function of Bcr-Abl. The long-term objectives are to determine whether the oncogenic function of Bcr-Abl is regulated and/or mediated by its binding proteins, and if so, whether the malignant potential of Bcr-Abl can be mitigated by controlling these interactions. Such information will help to elucidate the leukemogenic pathway activated by Bcr-Abl and help to develop therapeutic drugs for human leukemia. Accordingly, the specific aims of the project are as follows: (1) To test the hypothesis that the association of Grb2 or other ABPs with Bcr-Abl is required for the transformation of Bcr-Abl via examining the effect of the mutations in Bcr-Abl that interrupt ABP- binding on neoplastic transformation; (2) To test the hypothesis that cells of hematopoietic lineage derived from CML patients contain a unique set of ABPs by identifying the potential targets of Bcr-Abl from CML cells; (3) To test the hypothesis that the malignant potential of Bcr-Abl can be mitigated by interrupting the interaction between Bcr-Abl and ABPs in trans by examining the ability of overexpression of ABPs or their mutant polypeptides to block cellular transformation.