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ABI-1 GENE PRODUCT IN SIGNAL TRANSDUCTION & TRANSFORMATION BY VABL & BCR-ABL

ABI-1 GENE PRODUCT IN SIGNAL TRANSDUCTION & TRANSFORMATION BY VABL & BCR-ABL
信号转导中的 ABI-1 基因产物
批准号:
6103392
负责人:
STEPHEN Paine GOFF
金额:
$11.73万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-01-20 至 1999-12-31

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中文摘要
翻译
本研究描述了确定 Abi-l 功能的实验 (Abelson interactor-1) 蛋白在致癌转化中的作用 Abelson 癌蛋白 v-Abl 和 BCR-ABL。阿贝尔森基因编码 细胞质酪氨酸激酶; v-Abl 是一种激活形式,由 阿贝尔森鼠白血病病毒,引起小鼠前 B 淋巴瘤, BCR-ABL 是一种效力较弱的版本,可导致慢性骨髓性骨髓瘤 白血病(CML),有时还有急性淋巴细胞白血病(ALL) 人类。 Abi-l 最初是使用酵母双杂交体鉴定的 系统作为一种新型 SH3 蛋白,与富含脯氨酸的 C 末端结合 v-Abl 尾部并抑制其转化活性。遗传和 将进行生化实验以确定哪些信号 转导途径受 Abi-1 蛋白控制或抑制 或被 Abi-1 蛋白抑制。表达高水平的细胞系 将检查野生型或突变型 Abi-1 的激活情况 下游靶基因(c-myc、DHFR);用于激活下游 靶基因(c-myc、DHFR):用于激活已知的 PDGF 途径(Ras、 PLCg、PI3K);用于刺激细胞周期调节蛋白;并为 Jak/Stat 和 Crkl 蛋白的磷酸化和激活。人类 将测试来自 CML 患者的肿瘤样本以确定 Abi-1 蛋白以及与 BCR-ABL 结合的部分。最后,v-的突变体 Abl 将产生该转化活动。酵母双杂交 系统将用于分离与一个伴侣结合但不结合的突变体 携带相关突变的病毒将被传播给其他人 测试了细胞系和小鼠的转化活性。这些 实验应该有助于确定各种途径中的哪一种发出 来自 Abl 激酶的致癌转化需要。这些 实验可以提供有关感应和 人类 CML 和 ALL 的疾病进展。
英文摘要
This study describes experiments to determine the functions of the Abi-l (Abelson interactor-1) protein in oncogenic transformation by the Abelson oncoproteins v-Abl and BCR-ABL. The Abelson gene encodes a cytoplasmic tyrosine kinase; v-Abl is an activated form expressed by the Abelson murine leukemia virus, causing a pre-B lymphoma in mice, which BCR-ABL is a less potent version responsible for chronic myelogenous leukemia (CML) and, sometimes, acute lymphocytic leukemia (ALL) in humans. Abi-l was originally identified using the yeast two-hybrid system as a novel SH3 protein that binds to the proline-rich C terminal tail of v-Abl and suppresses its transforming activity. Genetic and biochemical experiments will be performed to determine which signal transduction pathways are controlled or inhibited by the Abi-1 protein or inhibited by the Abi-1 proteins. Cell lines expressing high levels of either the wild-type or mutant Abi-1 will be examined for activation of downstream target genes (c-myc, DHFR); for activation of downstream target genes (c-myc, DHFR): for activation of known PDGF pathways (Ras, PLCg, PI3K); for stimulation of cell cycle regulatory proteins; and for phosphorylation and activation of Jak/Stat and Crkl proteins. Human tumor samples from CML patients will be tested to determine the level of Abi-1 protein, and the fraction bound to BCR-ABL. Finally, mutants of v- Abl will be generated that transforming activity. The yeast two-hybrid system will be used to isolate mutants that bind to one partner but not to others, and viruses carrying the relevant mutations will then be tested for transforming activity in cell lines and mice. These experiments should help identify which of the various pathways emanating from the Abl kinase are required for oncogenic transformation. These experiments may provide important information about the induction and progression of disease in human CML and ALL.
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