对于Cdk2独立的S相进入,需要在环林E中提供一个中心体局部化信号
Yutaka Matsumoto1, James L Maller
1Howard Hughes Medical Institute (HHMI) and Department of Pharmacology, University of Colorado School of Medicine, Denver, CO 80262, USA.
Science (New York, N.Y.)
|October 30, 2004
概括
循环蛋白E中新发现的一种中心体局部化信号 (CLS) 对于DNA合成和细胞周期进展至关重要. 这种信号使得循环蛋白E能够独立于Cdk2促进S阶段的进入,为癌细胞增殖提供了新的见解.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 过多的环林E-Cdk2活性加速细胞周期S阶段的进入,并促进多体化,可能导致癌症的基因组不稳定性.
- 环素E在调节细胞循环进展方面发挥着关键作用,但其精确的机制,特别是与中心体功能相关的机制,尚未完全理解.
研究的目的:
- 识别和描述E环素中特定域的作用,这些域负责E环素的中心体局部化.
- 调查环素E的中心体局部化对DNA合成和细胞周期进展的贡献.
- 确定环素E对S相进入的影响是否取决于其与Cdk2的相互作用或其中枢体向.
主要方法:
- 局部定向的突变发生能产生缺乏功能中心体局部化信号 (CLS) 的环林E突变体.
- 野生型和突变型环林E和细胞系中全长蛋白质的表达.
- 免疫光显微镜用于评估中心体中的蛋白质定位.
- 流细胞计分析DNA合成和细胞周期进展.
- 生物化学试验评估Cdk2结合活性.
主要成果:
- 鉴定出环林E中的20个氨基酸区域是中心体局部化信号 (CLS),对于中心体向和促进DNA合成至关重要.
- 野生类型的CLS,但不是突变,局部化到中心体,抑制内源性环林E/A局部化,并抑制DNA合成.
- 宫外环林E局部化到中心体,加速S相进入,即使Cdk2结合被废除,但不是当CLS发生突变时.
结论:
- 循环E具有一个模块化的中心体向域 (CLS),这对其功能至关重要.
- 环素E的中体局部定位对于促进S阶段进入至关重要,以Cdk2独立的方式起作用.
- 准环林E CLS可能提供一种新的策略来控制癌细胞增殖.
相关概念视频
01:45Positive Regulator Molecules
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
02:39Positive Regulator Molecules
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
02:15M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
02:17Separation of Sister Chromatids
At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...
At the onset of anaphase, separase, a proteolytic enzyme, is...
00:50Anaphase Promoting Complex
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...