DIFFERENTIATION SIGNAL TRANSDUCTION IN MYELOID LEUKEMIA

粒细胞白血病的分化信号转导

• 批准号: 3079832
• 负责人: RICHARD M STONE
• 金额: $ 8.97万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3079832
• 关键词: 1,25 dihydroxycholecalciferol; arachidonate; biological signal transduction; cell differentiation; clone cells; fatty acid metabolism; gene expression; genetic transcription; genetic translation; human subject; messenger RNA; molecular oncology; monocyte; myelogenous leukemia; myeloid stem cell; phorbols; phospholipase C; protein kinase C; protooncogene

The overall objective of this proposal is to gain an understanding of signal transduction events that result in monocytic differentiation of human myeloid leukemia cells. Previous studies from this laboratory have indicated that activation of protein kinase C is associated with the appearance of a monocytic phenotype and expression of the c-fms proto- oncogene. The c-fms gene product, a transmembrane protein with tyrosine kinase activity, is identical to the CSF-1 receptor. Since CSF-1 is required for the proliferation and differentiation of monocytes, regulation of the c-fms gene is a crucial event for maturation along this lineage. The proposed studies will focus on the signaling mechanisms responsible for controlling the expression of this gene. Certain insights are now available regarding the regulation of c-fms expression. While studies with phorbol esters, bryostatin 1, and phospholipase C have implicated the activation of protein kinase C, other events may be involved in controlling the level of c-fms transcripts. In this regard, recent work has indicated that the production of arachidonic acid metabolites associated with protein kinase C activation is responsible for signals that regulate c-fms expression. Moreover, recent studies have demonstrated that the level of c-fms transcripts is controlled postranscriptionally by a labile protein. These findings have provided the experimental basis for the proposed studies. The proposed work will monitor the role of protein kinase C in the induction of c-fms during monocytic differentiation (Specific Aim 1) by employing agents known to activate and inhibit this enzyme. Furthermore, agents which are known to induce c-fms mRNA (such as 1, 25 dihydroxyvitamin D3) will metabolism in the regulation of c-fms expression will be monitored (Specific Aim 2) with the use of agents which affect this pathway at various steps. Transcriptional activation and posttranscriptional regulation of c-fms gene expression (Specific Aim 3) will be studied as events induced by signaling pathways identified monocytic differentiation in myeloid cell lines and studied for c-fms expression, protein kinase C activation, and arachidonic acid release (Specific Aim 4). These studies should provide insights regarding signaling events associated with c-fms expression and monocytic differentiation of myeloid leukemia cells. The results of these studies may also be applicable toward defining events which result in a block in differentiation characterized by clonogenic cells in human acute myeloid leukemia.

本提案的总体目标是了解 导致单核细胞分化的信号转导事件 人类骨髓白血病细胞。 该实验室以前的研究表明， 表明蛋白激酶C的激活与 单核细胞表型的出现和c-fms原核表达， 癌基因 c-fms基因产物是一种酪氨酸蛋白 激酶活性，与CSF-1受体相同。 由于CSF-1是 单核细胞增殖和分化所需的调节 c-fms基因的缺失是沿着该谱系成熟的关键事件。 拟议的研究将集中在信号机制负责 控制这个基因的表达。 关于c-fms的监管，现在有了一些见解 表情 虽然用佛波醇酯、苔藓抑素1和 磷脂酶C与蛋白激酶C的激活有关， 事件可能参与控制c-fms转录物的水平。 在 在这方面，最近的研究表明，花生四烯酸的生产 与蛋白激酶C激活相关的酸性代谢产物是负责 用于调节c-fms表达的信号。 此外，最近的研究表明， 表明c-fms转录物的水平受到控制， 由不稳定的蛋白质进行后转录。 这些发现提供了 为拟议的研究提供实验基础。 拟议的工作将监测蛋白激酶C的作用， 单核细胞分化过程中c-fms的诱导（特异性目的1） 使用已知激活和抑制这种酶的试剂。 此外，委员会认为， 已知诱导c-fms mRNA的试剂（如1，25-二羟基维生素 D3）将代谢在c-fms表达的调节中进行监测 （具体目标2）使用影响这一途径的药物， 各种步骤。 转录激活和转录后 将研究c-fms基因表达的调控（具体目标3）， 由信号通路诱导的事件鉴定单核细胞分化 在骨髓细胞系中，研究了c-fms表达、蛋白激酶C 活化和花生四烯酸释放（具体目标4）。 这些研究应该提供有关信号事件相关的见解 c-fms表达与髓系白血病单核细胞分化的关系 细胞 这些研究的结果也可能适用于定义 导致分化阻滞的事件，其特征在于 人急性髓性白血病的克隆形成细胞