Regulation of mitotic Aur-A-kinase in checkpoint arrest

检查点停滞中有丝分裂 Aur-A-激酶的调节

• 批准号: 6868853
• 负责人: QUENTIN Q LIU
• 金额: $ 5.75万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868853
• 关键词: DNA damage; Xenopus; Xenopus oocyte; apoptosis; cell cycle; cell cycle proteins; cell growth regulation; chromosome movement; embryogenesis; enzyme induction /repression; enzyme mechanism; immunoprecipitation; kinase inhibitor; p53 gene /protein; postdoctoral investigator; protein structure function; serine threonine protein kinase; soma; terminal nick end labeling; western blottings

DESCRIPTION (provided by applicant): The mitotic kinase, Aurora-A (Aur-A), is important for accurate chromosome segregation. AurA is amplified or over expressed in most of the common cancers. Experimentally, forced over-expression of Aur-A results in aneuploidy, cellular transformation, and tumor formation in mice. New evidence suggests overexpression of Aur-A may override a DNA damage-induced G2 checkpoint arrest. Xenopus egg cycling extracts, which carry out many cell cycle events in vitro, are a convenient and powerful system to investigate the roles of Aur-A in DNA damage checkpoint control. In the proposed work, I will first determine the exact timing of AurA activation in relation to cdc2 activation and the G2tM transition in cycling extracts. I will then ask if DNA damage checkpoints, which block activation of cdc2, also inhibit Aur-A activation. If so, I will determine if this inhibition depends on p53. I will lastly test how the over-expression of AurA may override checkpoint arrest in mammalian somatic cells. These experiments will address the potential important role of Aur- A in proceeding into mitosis under both normal and checkpoint-arrested cell cycle. Studying the potential role of Aur-A in DNA damage checkpoint should provide new insights for understanding the underlying mechanisms for both tumorigenesis and resistance to DNA damage chemotherapy.

描述（由申请人提供）： 有丝分裂激酶 Aurora-A (Aur-A) 对于准确的染色体分离非常重要。 AurA 在大多数常见癌症中都会扩增或过度表达。实验上，Aur-A 的强制过度表达会导致小鼠非整倍体、细胞转化和肿瘤形成。新证据表明 Aur-A 的过度表达可能会推翻 DNA 损伤引起的 G2 检查点停滞。非洲爪蟾卵循环提取物可在体外进行许多细胞周期事件，是研究 Aur-A 在 DNA 损伤检查点控制中作用的便捷而强大的系统。在拟议的工作中，我将首先确定 AurA 激活与 cdc2 激活和循环提取物中 G2tM 转换相关的确切时间。然后我会问，阻止 cdc2 激活的 DNA 损伤检查点是否也会抑制 Aur-A 激活。如果是这样，我将确定这种抑制是否取决于 p53。最后我将测试 AurA 的过度表达如何克服哺乳动物体细胞中的检查点停滞。这些实验将探讨 Aur-A 在正常细胞周期和检查点停滞细胞周期下进入有丝分裂过程中的潜在重要作用。研究 Aur-A 在 DNA 损伤检查点中的潜在作用应该为理解肿瘤发生和 DNA 损伤化疗耐药的潜在机制提供新的见解。