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.

这项建议的总体目标是了解 导致单核细胞分化的信号转导事件 人髓系白血病细胞。这个实验室之前的研究已经 研究表明，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 致癌基因。C-fms基因产物，一种含酪氨酸的跨膜蛋白 激酶活性，与脑脊液-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基因的突变是沿着这一谱系成熟的关键事件。 拟议的研究将集中在负责的信号机制上 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。而对佛波酯、Bryostatin 1和 磷脂酶C参与了蛋白激酶C的激活，其他 事件可能参与控制c-FMS转录本的水平。在……里面 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 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制的。 通过一种不稳定的蛋白质转录后。这些发现为我们提供了 为拟开展的研究奠定了实验基础。 这项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(特异性目标1) 使用已知的激活和抑制这种酶的试剂。此外， 已知可诱导c-FMS基因表达的药物(如1，25二羟基维生素C D3)将监测c-fms表达调节中的代谢 (特定目标2)使用影响这一途径的药物 各种步骤。转录激活和转录后激活 C-fms基因表达的调控(特定目标3)将研究如下 识别单核细胞分化的信号通路诱导的事件 在髓系细胞系中，并研究了c-fms的表达，蛋白激酶C 激活和花生四烯酸释放(具体目标4)。 这些研究应该提供有关相关信号事件的见解 髓系白血病c-FMS表达与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 导致分化受阻的事件的特征是 人急性髓系白血病中的克隆形成细胞。