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A family of protein kinases involved in cell cycle checkpoints.

机译：参与细胞周期检查点的蛋白激酶家族。

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摘要

Cells require the precise coordination of events to execute the cell cycle, even under normal conditions. To complicate matters, additional circumstances such as damaged DNA, incomplete replication, or nutrient deprivation can inflict significant damage if the cell cycle is not temporarily arrested to allow for recovery. Arresting the cell cycle under these conditions requires a cell cycle checkpoint, a signaling pathway that recognizes damage or deficiencies and activates the necessary responses, including the cell cycle arrest. The examination of many different checkpoint pathways have identified in each a distinctive high molecular weight protein with some homology to protein and lipid kinases, yet overall these checkpoint genes form a discrete family of its own. This thesis will discuss three of these checkpoint kinases, including their identification and studies of their mechanism of action in their respective pathways.;The identification of the mammalian target of the drug rapamycin, FRAP (FKBP12-rapamycin associated protein), was followed by the molecular cloning of its cDNA. This sequence was discovered to belong to a novel family of genes, which included two similar yeast kinases involved in the checkpoint response to nutrient deprivation. A molecular cloning based on finding additional homologues of FRAP identified a second novel human gene, FRP1 (FRAP-related protein). Its sequence showed similarity not only to FRAP but more closely to other members of this family that were involved in checkpoint responses to DNA damage.;Studies on a third checkpoint gene and another member of this kinase family, the Saccharomyces cerevisiae MEC1, showed that its kinase domain and highly conserved C-terminal tail domain were required for its checkpoint activity. Furthermore, overexpression of an inactive allele of MEC1 can cause a dominant-negative effect on the cell. Genetic studies identified two targets of this inhibition, one related to its checkpoint function and the other to a function essential for normal growth.
机译：即使在正常条件下，细胞也需要事件的精确协调才能执行细胞周期。使事情变得复杂的是，如果细胞周期没有被暂时阻止以便恢复，那么诸如DNA受损，复制不完全或营养缺乏等其他情况可能会造成重大损害。在这些条件下阻止细胞周期需要一个细胞周期检查点，这是一个识别损伤或缺陷并激活必要的响应（包括细胞周期停滞）的信号传导途径。对许多不同检查点途径的检查已在每种蛋白质中鉴定出了一种独特的高分子量蛋白质，该蛋白质与蛋白质和脂质激酶具有某些同源性，但总体而言，这些检查点基因形成了自己的离散家族。本论文将讨论其中的三种检查点激酶，包括它们的鉴定以及它们在各自途径中的作用机理的研究。;对雷帕霉素药物哺乳动物靶标FRAP（FKBP12-雷帕霉素相关蛋白）的鉴定，随后是其cDNA的分子克隆。发现该序列属于一个新的基因家族，包括两个相似的酵母激酶，参与了对营养剥夺的检查站反应。基于发现FRAP的其他同源物的分子克隆鉴定了第二个新的人类基因FRP1（FRAP相关蛋白）。其序列不仅显示出与FRAP的相似性，而且还与该家族的其他成员（涉及DNA损伤的检查点应答）更相似。;对第三个检查点基因和该激酶家族的另一个成员酿酒酵母（Saccharomyces cerevisiae）MEC1的研究表明激酶结构域和高度保守的C末端尾部结构域是其检查点活性所必需的。此外，MEC1的无活性等位基因的过表达可导致对细胞的显性负作用。遗传学研究确定了这种抑制作用的两个目标，一个与其抑制点功能有关，另一个与正常生长必不可少的功能有关。

著录项

  • 作者

    Shin, Tae Bum.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Biology Molecular.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 1998
  • 页码 136 p.
  • 总页数 136
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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