KINASE ENCODING PROTO-ONCOGENES IN IL-2 SIGNAL TRANSDUCT

IL-2 信号转导中激酶编码原癌基因

• 批准号: 3199411
• 负责人: JOHN C REED
• 金额: $ 12.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3199411
• 关键词: T lymphocyte; binding proteins; biological signal transduction; cell growth regulation; gene mutation; genetic manipulation; growth factor receptors; interleukin 2; intracellular transport; laboratory rabbit; lymphocyte proliferation; mitogens; molecular cloning; oncogenes; phosphatidylinositols; phospholipase C; phosphorylation; platelet derived growth factor; protein signal sequence; protein tyrosine kinase; protooncogene; serine; threonine

The lymphokine interleukin-2 (IL2) is a critical regulator of lymphocyte growth and immune responses, and is beginning to find clinical uses for the treatment of cancer and immune disorders. Greater knowledge of the molecular mechanisms of IL2signal transduction, therefore, could ultimately contribute to improved pharmacological manipulation of in vivo immune responses or modulation of lymphoma and leukemic cell growth. Despite cloning of IL2 and its receptor genes and extensive investigations using a variety of approaches, little is known about the mechanisms of IL2-signal transduction. Unlike many other growth factor receptors, the IL2-binding molecules on lymphocytes lack tyrosine-kinase activity, and yet both tyrosine and serine/ threonine phosphorylation of intracellular proteins are rapid events in IL2-stimulated T-cells. Clearly, therefore, IL2 and its receptor must regulate the activity of kinases in lymphocytes. Recently, we have found that IL2 induces tyrosine phosphorylation and elevated activity of the RAF-1 kinase, a serine-threonine-specific kinase with homology to the transforming gene of MSV-3611 retrovirus. This kinase has been implicated previously in the regulation of mitogenesis and malignant transformation in several types of cells, including lymphocytes. We will explore the mechanisms responsible for phosphorylation and activation of the RAF-1 kinase in IL2-stimulated T-cells. Further we will investigate the effects of this kinase on the regulation of T-cell growth. These studies will contribute to an improved understanding of the intracellular mechanisms of IL2 action, and may provide insights into the growth factor/oncogene networks involved in the development and progression of leukemias and lymphomas.

淋巴因子白细胞介素-2（IL-2）是一种重要的调节因子， 淋巴细胞生长和免疫反应，并开始发现临床 用于治疗癌症和免疫疾病的用途。 更多的知识 IL 2信号转导的分子机制，因此， 最终有助于改善体内的药理学操作 免疫应答或调节淋巴瘤和白血病细胞生长。 尽管IL 2及其受体基因的克隆和广泛的 使用各种方法进行调查，对 IL 2信号转导机制。 与其他许多生长因子不同， 受体，淋巴细胞上的IL 2结合分子缺乏酪氨酸激酶 活性，但酪氨酸和丝氨酸/苏氨酸磷酸化， 细胞内蛋白是IL 2刺激的T细胞中的快速事件。 因此，很明显，IL 2及其受体必须调节 淋巴细胞中的激酶。 最近，我们发现IL 2诱导酪氨酸磷酸化， 和RAF-1激酶活性升高，RAF-1激酶是丝氨酸-苏氨酸特异性 与MSV-3611逆转录病毒的转化基因同源。 这种激酶以前曾参与调节 有丝分裂和几种类型细胞的恶性转化， 包括淋巴细胞。 我们将探讨负责 RAF-1激酶的磷酸化和活化 T细胞 我们将进一步研究这种激酶对细胞凋亡的影响。 调节T细胞生长。 这些研究将有助于 提高对IL 2作用的细胞内机制的理解，以及 可能提供深入了解生长因子/癌基因网络参与 白血病和淋巴瘤的发展和进展。