CHROMATIN TARGETS FOR CANCER THERAPY

描述：(申请人描述) 腺病毒ELA癌蛋白在芽殖酵母中的表达 揭示涉及癌蛋白作用的新途径的有用模型。 值得注意的是，多蛋白复合体(SWI/SNF和HAT复合体)介导 染色质重塑和转录调控是EIA的目标， 这导致了一种强有力的预测，那就是颠覆它们的人类同行 在癌症的发展过程中起着重要作用。事实上，有来自人类的证据 癌症的发展与丢失或 几种SWI/SNF和HAT组分编码基因的失调 复合体。鉴于“染色质动力学”在细胞中的明确作用 调控及其在肿瘤发生中的基因参与， 控制染色质功能可能包含抗癌药物的有用靶点 心理治疗。这项提案旨在延长之前关于肿瘤发生相关的工作 酵母中的途径，并鉴定具有抗癌作用的新化合物 治疗潜力。染色质有明确缺陷的酵母菌株 改建功能将受到两个高吞吐量屏幕的影响 图书馆：约2000种化合物的“多样性集合” 国家癌症研究所的发展治疗计划和一个图书馆 约6000种植物乙醇提取物，可通过 弗吉尼亚大学马基细胞信号中心。久经考验的 酿酒酵母在阐明与肿瘤相关的新基因方面的应用 途径将允许遗传解剖新的先导化合物的作用 从毒品筛查来的。先导化合物将在哺乳动物细胞中进行进一步测试 培养系统，以检查其作为治疗剂的潜力，以及他们的 对哺乳动物染色质动力学的特殊影响。

DESCRIPTION: (Applicant's Description) Expression of the adenovirus ElA oncoprotein in budding yeast has provided a useful model for uncovering novel pathways involved in oncoprotein action. Remarkably, multiprotein complexes (SWI/SNF and HAT complexes) that mediate chromatin remodeling and transcriptional regulation are targeted by EIA, leading to the strong prediction that disruption their human counterparts is important in the development of cancer. Indeed, there is evidence from human systems that the development of cancer is associated with loss or disregulation of genes encoding components of several SWI/SNF and HAT complexes. Given the clear role of "chromatin dynamics" in cellular regulation, and its genetic involvement in oncogenesis, the pathways which control chromatin function may contain useful targets for anti-cancer drug therapy. This proposal seeks to extend previous work on oncogenesis-related pathways in yeast, and to identify novel compounds with anti-cancer therapeutic potential. Yeast strains with defined defects in chromatin remodeling functions will be subjected to high throughput screens of two libraries: The "Diversity Set" of approximately 2000 compounds from the National Cancer Institute's Developmental Therapeutics Program, and a library of approximately 6000 ethanolic botanical extracts available through the Markey Center for Cell Signaling at the University of Virginia. The proven utility of Saccharomyces cerevisiae for illuminating novel oncogenesis-related pathways will allow genetic dissection of the action of novel lead compounds from the drug screens. Lead compounds will be tested further in mammalian cell culture systems to examine their potential as therapeutic agents, and their specific effects on mammalian chromatin dynamics.