CELL CYCLE CHECKPOINT THAT MONITORS MORPHOGENESIS

监测形态发生的细胞周期检查点

• 批准号: 6619423
• 负责人: DANIEL J LEW
• 金额: $ 26.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619423
• 关键词: biological signal transduction; cell communication molecule; cell cycle; cell cycle proteins; cell growth regulation; cellular polarity; cyclin dependent kinase; electrophoresis; fungal proteins; gene expression; histogenesis; molecular cloning; phosphorylation; protein kinase C; protein structure function; protein tyrosine kinase; radionuclides; yeasts

Cancer cells must acquire multiple mutations to evade the many restraints that prevent uncontrolled proliferation. Normal cells are vigilant in maintaining genome integrity (i.e. preventing mutations), but one hallmark of cancer cells is a defect in such self-surveillance and hence genome instability. Checkpoint controls that govern entry into mitosis are essential for maintaining genome integrity during cell proliferation. The Wee1 family kinases that inhibit cdc25 are among the targets for these checkpoints in mammalian cells and in yeast, but the basis for their regulation remains unclear. In budding yeast, the wee1 relative Swe1p is employed by the morphogenesis checkpoint, responding to perturbations of the actin cytoskeleton. We have identified a novel pathway controlling Swe1p degradation, and one aim of this proposal is to understand how Swe1p is targeted for degradation during the normal cell cycle, and how this process is halted by the checkpoint. The upstream pathways whereby cells can monitor the organization of the actin cytoskeleton will also be investigated. Although the morphogenesis checkpoint has not yet been identified in cells other than yeast, appropriate responses of mammalian cells to geometrical and mechanical features of their microenvironment are thought to involve sensing of similar types of cytoskeletal information. The metastatic potential of cancer cells increases upon derangement of these pathways, and the proposed studies will therefore provide new insight into cancer progression, and may yield potential targets for therapeutic intervention.

癌细胞必须获得多种突变才能逃避多种攻击 防止不受控制的扩散的限制。正常细胞保持警惕 维持基因组完整性（即防止突变），但有一个标志 癌细胞的自我监控存在缺陷，因此基因组也存在缺陷 不稳定。控制进入有丝分裂的检查点控制至关重要 用于在细胞增殖过程中维持基因组完整性。 Wee1家族 抑制 cdc25 的激酶是这些检查点的靶标之一 哺乳动物细胞和酵母中，但它们的调节基础仍然存在 不清楚。在芽殖酵母中， wee1 相关 Swe1p 被 形态发生检查点，响应肌动蛋白的扰动 细胞骨架。我们已经确定了控制 Swe1p 降解的新途径， 该提案的目的之一是了解 Swe1p 的目标是 正常细胞周期期间的降解，以及如何通过 检查站。细胞可以监控组织的上游途径 肌动蛋白细胞骨架也将被研究。虽然形态发生 尚未在酵母以外的细胞中鉴定出检查点，适当 哺乳动物细胞对其几何和机械特征的反应 微环境被认为涉及类似类型的感知 细胞骨架信息。癌细胞的转移潜力增加 一旦这些途径被打乱，拟议的研究将因此 提供对癌症进展的新见解，并可能产生潜在的目标 进行治疗干预。