Signal Transduction Events and the Regulation of Cell Gr

信号转导事件与细胞Gr的调控

• 批准号: 6756753
• 负责人: JANE B TREPEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6756753
• 关键词: acyltransferase; antineoplastics; biological signal transduction; breast neoplasms; cell cell interaction; cell cycle; cell growth regulation; cell proliferation; cellular oncology; confocal scanning microscopy; cyclic AMP; cyclins; cytoskeleton; enzyme inhibitors; genetic regulation; human tissue; immunoprecipitation; neoplastic growth; oncoprotein p21; prostate neoplasms; protein localization; tumor suppressor genes

This project is designed to develop a new approach to cancer treatment through the study of growth-regulatory signal transduction events that identify molecular targets for anticancer drug development. This work is currently focused on (1) histone deacetylase as a target for anticancer drug development, and (2) the molecular mechanism of hematopoietic cell regulation by beta-catenin and the identification of beta-catenin as a target in hematologic malignancies. (1) Our basic research on signal transduction pathways that can inhibit the growth of hormone-refractory prostate cancer cells led us to the identification of histone deacetylase as a critical target in this neoplasm. We are taking a two-pronged approach to this project. Firstly we are performing basic studies of the impact of signaling pathways on histone acetylase complexes regulating the promoter of the cyclin-dependent kinase inhibitor p21, which is an important transcriptional target of the anticancer histone deacetylase inhibitors. Secondly, we are performing all of the translational science and pharmacodynamic studies on the phase I trial of a new histone deacetylase inhibitor MS-275, that is being run in solid tumors at the NCI and in hematologic malignancies at the University of Maryland Cancer Center. (2) While studying the anticancer action of lovastatin, a drug that was brought to phase I clinical trial at the NCI as a direct translation of our research, we found that a critical determinant of sensitivity to the proapoptotic activity of lovastatin was the integrity of beta-catenin protein. This led us to examine the role of beta-catenin in apoptosis. We used hematologic malignancies as our model and found that beta-catenin plays an unexpectedly vital role in these cells. Our data demonstrate that beta-catenin regulates leukemia cell survival, proliferation, and adhesive properties. These data identify beta-catenin as a novel target for anticancer drug development in hematologic malignancies. We are also studying the role of beta-catenin in mature peripheral lymphocytes, and have evidence that beta-catenin is crucial in peripheral T-cell activation. Our data suggest the hypothesis that a burst of beta-catenin signaling is required for T-cell activation, and that failure to appropriately down-regulate beta-catenin signaling is transforming.

该项目旨在通过研究生长调节信号转导事件来确定抗癌药物开发的分子靶点，从而开发一种新的癌症治疗方法。这项工作目前主要集中在(1)组蛋白脱乙酰酶作为抗肿瘤药物开发的靶点，以及(2)β-连环蛋白调节造血细胞的分子机制以及确定β-连环蛋白作为血液系统恶性肿瘤的靶标。 (1)我们对抑制激素耐药的前列腺癌细胞生长的信号转导通路的基础研究使我们确定组蛋白脱乙酰酶是该肿瘤的关键靶点。我们对这个项目采取了双管齐下的方法。首先，我们正在进行基础研究，研究信号通路对组蛋白乙酰化酶复合体调控周期蛋白依赖的激酶抑制物p21启动子的影响，p21是抗癌组蛋白去乙酰化酶抑制剂的重要转录靶点。其次，我们正在进行一种新的组蛋白去乙酰酶抑制剂MS-275的I期试验的所有翻译科学和药效学研究，该试验正在NCI的实体肿瘤和马里兰大学癌症中心的血液恶性肿瘤中运行。(2)在研究洛伐他汀的抗癌作用时，我们发现，对洛伐他汀促凋亡活性敏感性的一个关键决定因素是β-连环蛋白的完整性。洛伐他汀是在NCI进行I期临床试验的药物，是我们研究的直接翻译。这让我们研究了β-连环蛋白在细胞凋亡中的作用。我们使用恶性血液病作为我们的模型，发现β-连环蛋白在这些细胞中发挥着出人意料的重要作用。我们的数据表明，β-连环蛋白调节白血病细胞的存活、增殖和黏附特性。这些数据表明，β-连环蛋白是治疗血液系统恶性肿瘤的抗癌药物开发的新靶点。我们还在研究β-连环蛋白在成熟外周淋巴细胞中的作用，并有证据表明，β-连环蛋白在外周T细胞激活中起关键作用。我们的数据提出了一种假设，即T细胞激活需要一系列β-连环蛋白信号，而未能适当下调β-连环蛋白信号正在转变。