CELL CYCLE CHECKPOINTS IN THE XENOPUS EMBRYO

非洲爪蟾胚胎中的细胞周期检查点

• 批准号: 6096921
• 负责人: JILL C SIBLE
• 金额: $ 13.42万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6096921
• 关键词: Xenopus; Xenopus oocyte; apoptosis; biological signal transduction; cell cycle; cell growth regulation; developmental genetics; early embryonic stage; embryogenesis; vertebrate embryology

Checkpoints in the eukaryotic cell cycle maintain the integrity of the genome by arresting the cell cycle when DNA is damaged or incompletely replicated. Checkpoint pathways converge upon the activities of cyclin-dependent kinases (Cdks), enzymes that catalyze cell cycle progression. Early embryonic cell cycles of the frog Xenopus laevis provide rare examples of non-pathological cell divisions that lack checkpoints. Following fertilization, the Xenopus egg begins twelve rapid and synchronous cell cycles that oscillate between DNA replication and mitosis without growth, gap phases, or checkpoints. These early cell cycles proceed "unchecked" when DNA is damaged or DNA replication is blocked. Completion of the twelfth cleavage marks the midblastula transition (MBT). At the MBT, embryonic gene expression begins, and the cell cycle remodels, lengthening as it acquires the gap phases and checkpoints of a typical adult cell cycle. The proposed project will investigate the role of XChk1 during embryogenesis of Xenopus. XChk1 is homologous to mammalian and yeast Chk1, which inactivate Cdks to maintain cell cycle arrest. XChk1 is also homologous to Grp1, which functions in timing the MBT during Drosophila development. XChk1 function will be investigated during the remodeling cell cycles of the Xenopus embryo. Specific aims are to investigate 1) when XChk1 signaling becomes operational, 2) the requirement for XChk1 in DNA damage and DNA replication checkpoints, and 3) the relationship between XChk1 and a developmental program of apoptosis, 4) the role of XChk1 in timing the MBT, and 5) the targets of XChk1 signaling. The embryonic cell divisions of Xenopus, which remodel from rapid to regulated cell cycles, provide a uniquely rich system in which to investigate the engagement of checkpoints. A better understanding of the signaling pathways that mediate cell cycle checkpoints during frog embryogenesis may help us to modulate other atypical cell cycles. These include the exuberant cell cycles of cancer, the failing cell cycles of aging and senescence, and the usurped cell cycles of infectious disease.

真核细胞周期中的检查点通过阻止DNA受损或不完全复制时通过阻止细胞周期来保持基因组的完整性。 检查点途径会融合细胞周期蛋白依赖性激酶（CDKS）的活性，即催化细胞周期进程的酶。 青蛙爪诺乱的早期胚胎细胞周期提供了缺乏检查点的非病理细胞分裂的罕见实例。 受精后，爪蟾卵开始了十二个快速和同步细胞周期，这些细胞周期在没有生长，间隙阶段或检查点的DNA复制和有丝分裂之间振荡。 当DNA损坏或DNA复制被阻断时，这些早期的细胞周期将“未检查”。 第十二次裂解的完成标志着中等胸腔过渡（MBT）。 在MBT时，胚胎基因表达开始，并且细胞周期的重塑，随着获得典型成人细胞周期的间隙相和检查点的延长。拟议的项目将研究XCHK1在Xenopus的胚胎发生过程中的作用。 XCHK1与哺乳动物和酵母CHK1同源，它们使CDK灭活以维持细胞周期停滞。 XCHK1也与GRP1同源，GRP1在果蝇发育过程中起作用MBT。 XCHK1功能将在Xenopus胚胎的重塑细胞周期期间进行研究。 具体目的是调查1）当XCHK1信号转导开始运行时，2）XCHK1在DNA损伤和DNA复制检查点中的要求，以及3）XCHK1与凋亡的发展程序之间的关系，4）XCHK1在定时MBT中的作用，以及5）XCHK1信号的目标。从迅速调节的细胞周期重塑的Xenopus的胚胎细胞分裂提供了一个独特的系统，可以在其中研究检查点的参与度。 更好地了解介导青蛙胚胎发生过程中细胞周期检查点的信号传导途径可能有助于我们调节其他非典型细胞周期。 其中包括癌症的旺盛细胞周期，衰老和衰老的失败细胞周期以及传染病的细胞周期。