DIFFERENTIATION SIGNAL TRANSDUCTION IN MYELOID LEUKEMIA

粒细胞白血病的分化信号转导

• 批准号: 3079830
• 负责人: RICHARD M STONE
• 金额: $ 7.88万
• 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/3079830
• 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.

该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 人骨髓性白血病细胞。 该实验室之前的研究表明 表明蛋白激酶 C 的激活与 单核细胞表型的出现和 c-fms 原型的表达 癌基因。 c-fms基因产物，一种带有酪氨酸的跨膜蛋白 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 基因的表达是该谱系成熟的关键事件。 拟议的研究将重点关注负责的信号机制 控制该基因的表达。 现在可以获得有关 c-fms 监管的某些见解 表达。 虽然佛波酯、苔藓抑素 1 和 磷脂酶 C 涉及蛋白激酶 C 的激活，其他 事件可能涉及控制 c-fms 转录本的水平。 在 在这方面，最近的工作表明，花生四烯酸的生产 与蛋白激酶 C 激活相关的酸性代谢物是造成这种情况的原因 用于调节 c-fms 表达的信号。 此外，最近的研究表明 证明 c-fms 转录本的水平是受控的 由不稳定的蛋白质转录后。 这些发现提供了 拟议研究的实验基础。 拟议的工作将监测蛋白激酶 C 在 在单核细胞分化过程中诱导 c-fms（具体目标 1） 使用已知的激活和抑制该酶的试剂。 此外， 已知可诱导 c-fms mRNA 的药物（例如 1, 25 二羟基维生素 D3) 将监测 c-fms 表达调节中的代谢 （具体目标 2）使用影响该途径的药物 各种步骤。 转录激活和转录后 c-fms 基因表达的调控（具体目标 3）将被研究为 由信号通路诱导的事件确定了单核细胞分化 在骨髓细胞系中进行 c-fms 表达、蛋白激酶 C 的研究 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相关信号事件的见解 与c-fms表达和髓系白血病单核细胞分化相关 细胞。 这些研究的结果也可能适用于定义 导致分化受阻的事件，其特征为 人类急性髓系白血病的克隆细胞。