Exploring a New Pathway Regulating Mitosis

探索有丝分裂调控新途径

• 批准号: 7315651
• 负责人: Patrick G. Harran
• 金额: $ 33.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315651
• 关键词: Adverse effects; Animals; Antineoplastic Agents; Binding Sites; Biochemical; Biological Factors; Body Weight decreased; Cell division; Cells; Clinic; Complex; Cultured Cells; Development; Dominant-Negative Mutation; Dose; Embryo; Endopeptidases; Enzymes; Eukaryota; Eukaryotic Cell; Fibroblasts; Frequencies; Genetic; Human; Implant; In Vitro; Knockout Mice; Light; Malignant Neoplasms; Mediating; Metabolic; Microtubules; Mitosis; Mitotic; Mitotic Activity; Modeling; Monomeric GTP-Binding Proteins; Mus; Nature; Neutropenia; Normal Cell; Normal tissue morphology; Nude Mice; Oncogene Proteins; Pathway interactions; Peptide Hydrolases; Poisoning; Polyomavirus; Process; Property; Protein p53; Proteins; Proteolysis; Public Health; Recombinants; Regulation; Regulatory Pathway; Research; Research Personnel; Retroviridae; Role; Screening procedure; Signal Transduction; Structure; TP53 gene; Transferase; Transferase Gene; Tumor Suppressor Proteins; Work; X-Ray Crystallography; cancer cell; cancer therapy; design; diazonamide A; improved; in vitro Assay; in vivo; programs; protein function; reconstitution; research study; small molecule; small molecule libraries; three dimensional structure; tumor

Molecules that disrupt cell division are employed broadly in the treatment of cancer. The mechanism is effective because cancer cells replicate more frequently than normal. However, systemic poisoning of this kind has limits and side effects accompanying the use of conventional anti-mitotics are well discussed. For the past three years, we have studied a new type of small molecule anti-mitotic - a natural product called diazonamide A. It is highly effective at blocking spindle assembly in cell culture, and does so through a unique mechanism. The compound targets a previously unknown proteolyzed form of the metabolic enzyme ornthine 5-amino transferase (OAT). This truncated protein functions in the spindle assembly process, acting in concert with mitotic machinery downstream of the small GTPase Ran. Diazonamide inhibits this unexpected second function of OAT. A particularly exciting aspect of this discovery is that OAT-mediated spindle assembly is not required for normal development, as evidenced by the viability of OAT-null mice. Redundancies must exist, although OAT clearly supports rapid cell division. When a synthetic diazonamide is dosed intravenously in nude mice, one can fully regress implanted human tumors without noticeable neutropenia or weight loss. This is unprecedented for a small molecule anti-mitotic. Our proposal aims to explore the origins of this selectivity and chart what appears to be a new regulatory pathway controlling onset of spindle assemble in higher eukaryotes. We propose a rigorous biochemical analysis of OAT functions in mitosis as well as studies of animals lacking the OAT gene product on genetic backgrounds predisposed to cancer. This research is relevant to public health because it could help understand how a new cancer drug works and guide its use in the clinic.

破坏细胞分裂的分子广泛用于癌症的治疗。机制是 有效，因为癌细胞复制的频率比正常情况更频繁。但是，这是全身中毒 很好地讨论了伴随常规抗溶剂的副作用。为了 在过去的三年中，我们研究了一种新型的小分子抗丝质酸 - 一种天然产品，称为 重18zonamideA。它在阻断细胞培养中的纺锤体组件方面非常有效，并通过A 独特的机制。该化合物靶向代谢酶的先前未知的蛋白水解形式 Ornthine 5-氨基转移酶（OAT）。这种截断的蛋白质在主轴组装过程中起作用，作用 与小型GTPase下游的有丝分裂机械一起运行。重18zonamide抑制了这一点 燕麦的意外第二功能。这一发现的一个特别令人兴奋的方面是燕麦介导的 正常发育不需要主轴组件，这是燕麦无小鼠的生存能力所证明的。 冗余必须存在，尽管燕麦显然支持快速细胞分裂。当合成重射酰胺 在裸鼠中静脉注射，可以完全回归植入的人类肿瘤，而无需明显 中性粒细胞减少或体重减轻。对于小分子抗溶作剂，这是前所未有的。我们的建议旨在 探索这种选择性的起源，并绘制似乎是一种新的监管途径 纺锤体的发作在较高的真核生物中组装。我们提出了对燕麦的严格生化分析 有丝分裂的功能以及对缺乏燕麦基因产物在遗传背景上的动物的研究 容易患癌症。 这项研究与公共卫生有关，因为它可以帮助了解新的癌症药物如何工作 并指导其在诊所中的使用。