Role of RNA-Binding Proteins in BCR/ABL Leukemogenesis

RNA 结合蛋白在 BCR/ABL 白血病发生中的作用

• 批准号: 6683061
• 负责人: Danilo Perrotti
• 金额: $ 24.52万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683061
• 关键词: RNA binding protein; SCID mouse; SDS polyacrylamide gel electrophoresis; active sites; biological signal transduction; carcinogenesis; chronic myelogenous leukemia; confocal scanning microscopy; flow cytometry; genetic translation; green fluorescent proteins; hematopoietic stem cells; heterogeneous nuclear ribonucleoprotein; leukemia; mass spectrometry; messenger RNA; neoplasm /cancer genetics; phosphorylation; polymerase chain reaction; protein structure function; protooncogene; western blottings

DESCRIPTION (provided by applicant): Shuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey from the active site of transcription to that of translation; thus, gain or loss of their function in hematopoietic cells might result in altered hematopoiesis and/or emergence of leukemia. In BCR/ABL-expressing cells, there is a marked increase in the levels of different RNA binding proteins including FUS, hnRNP A1, hnRNP E2 and hnRNP K, four shuttling hnRNPs involved in the regulation of mRNA biogenesis, processing, nuclear export, and translation. Ectopic expression and/or inhibition of the activity of FUS, hnRNP A1 and hnRNP E2 affects the proliferation, survival, and differentiation of normal and BCR/ABL-expressing cells, suggesting that enhanced expression/activity of certain RNA-binding proteins plays an important but as yet unrecognized role in BCR/ABL leukemogenesis. Thus, the objective of this proposal is: 1) To investigate the mechanisms regulating hnRNP E2 and hnRNP A1 expression/function in BCR/ABL-expressing cells. 2) To identify hnRNP A1 and hnRNP E2-associated mRNAs encoding proteins differentially expressed in CML-blast crisis and CML-chronic phase cells. 3) To determine the BCR/ABL-dependent mechanisms regulating the expression/function of hnRNP K and determine whether hnRNP K function(s) is(are) required for BCR/ABL-induced leukemogenesis.

描述（由申请人提供）：从主动转录到翻译的旅程中，将HNRNPS的穿梭控制真核mRNA的命运；因此，其在造血细胞中功能的增益或丧失可能导致造血和/或白血病的出现改变。在表达BCR/表达ABL的细胞中，不同RNA结合蛋白的水平显着增加，包括FUS，HNRNP A1，HNRNP E2和HNRNP K，四个涉及MRNA生物生物生物生物生物生物的调节，加工，核出口，以及核出口和核出口，和核出口，和核的hnrnp翻译。异位表达和/或抑制FUS，HNRNP A1和HNRNP E2的活性会影响正常和表达BCR/ABL的细胞的增殖，存活和分化，这表明增强了某些RNA结合蛋白的表达/活性但是在BCR/ABL白血病发生中尚未识别的作用。因此，该提案的目的是：1）研究调节HNRNP E2和HNRNP A1表达/功能的机制。 2）鉴定HNRNP A1和HNRNP E2相关的mRNA，编码在CML-Blast危机和CML-奇语相细胞中差异表达的蛋白质。 3）确定调节HNRNP K的表达/功能的BCR/ABL依赖性机制，并确定BCR/ABL诱导的白血病发生是否需要HNRNP K函数（S）。