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有读书笔记有附件A Novel Protein Phosphatase 1-Dependent Spindle Checkpoint Silencing Mechanism

3 阿平 添加于 2009-9-1 04:23 | 4563 次阅读 | 0 个评论
  •  作 者

    Vanoosthuyse V, Hardwick KG
  •  摘 要

    The spindle checkpoint is a surveillance system acting in mitosis to delay anaphase onset until all chromosomes are properly attached to the mitotic spindle . When the checkpoint is activated, the Mad2 and Mad3 proteins directly bind and inhibit Cdc20, which is an essential activator of an E3 ubiquitin ligase known as the anaphase-promoting complex (APC) . When the checkpoint is satisfied, Cdc20-APC is activated and polyubiquitinates securin and cyclin, leading to the dissolution of sister chromatid cohesion and mitotic progression. Several protein kinases play critical roles in spindle checkpoint signaling, but the mechanism (or mechanisms) by which they inhibit mitotic progression remains unclear . Furthermore, it is not known whether their activity needs to be reversed by protein phosphatases before anaphase onset can occur. Here we employ fission yeast to show that Aurora (Ark1) kinase activity is directly required to maintain spindle checkpoint arrest, even in the presence of many unattached kinetochores. Upon Ark1 inhibition, checkpoint complexes are disassembled and cyclin B is rapidly degraded. Importantly, checkpoint silencing and cyclin B degradation require the kinetochore-localized isoform of protein phosphatase 1 (PP1(Dis2)). We propose that PP1(Dis2)-mediated dephosphorylation of checkpoint components forms a novel spindle checkpoint silencing mechanism.
  •  详细资料

    • 文献种类: Journal Article
    • 期刊名称: Current Biology : CB
    • 期刊缩写: Curr Biol
    • 期卷页: 2009
    • 地址: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK
    • ISBN: 1879-0445
    • 备注:PMID:19592249
  • 学科领域 生物医药 » 生物学

  •  所属群组

    蛋白组学  
  •  标 签

  • 相关链接 DOI URL 

  •  附 件

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  •  阿平 的文献笔记  订阅

    PP1活性是通过spindle checkpoint的必要条件

     

    ResearchBlogging.org

    个人感觉这篇文章很不错,采用了一个非常有说服力的模型,首先Aurora kinase和PP1一样,都在spindle checkpoint 里面扮演重要的角色,另外一方面,以前已经有不止一片文献描述Aurora kinase和PP1之间的互相拮抗作用,可以说是典型的一对激酶和蛋白磷酸酶。

    做酵母的优势就在于能够用温度来控制蛋白的表达,可以做很多温度敏感型的变异株来做实验。本文就采用一株既有microtubule depolymerization的变异,又有Aurora B的ATP结合位点变异。那么就是在一定温度下,既可以通过microtubule depolymerization让细胞停留在prometaphase,又可以通过添加ATP的衍生物1NMPP1来达到特异性、并且瞬间控制Aurora B活性的能力。

    通过这种方法,作者首先印证了在prometaphase时抑制Aurora B活性,可以导致细胞的mitotic exit,主要原因就是没有Aurora B活性,checkpoint就被克服了。作者通过观察mad2和mad3的减少来印证这一说法。当然,这个现象早就被证明过,没什么新鲜。

    接下去作者证明dis2(PP1的一个isoform)在Aurora B活性存在的情况下变异失活的话,并不会影响cyclin B的信号强度,简介说明checkpoint没有被改变.但是当Aurora B活性被抑制时,Dis2的变异造成原来会走出有丝分裂的细胞无法走出了,说明Dis2活性是满足checkpoint的必要条件。而非PP2A,Sds21(另外一个PP1 的isoform),最后证明这种mitotic exit的失败源自于anaphase-metaphase转换的延迟。

    AuroraB失活后,PP1所扮演的角色

    最后再次搬出有丝分裂中经典kinetochore movement假设图(不知道被多少人说过,这里主要增加了PP1的分量)。

    主要思想就是Aurora B的对kinetochore上的底物的活性决定于其与底物的距离,当kinetochore之间张力很小时,距离就近,底物受Aurora B的影响就大,受PP1的影响就小,所以主要变现为底物磷酸化。当达到足够张力(换句话说距离)的时候,Auroara B离kinetochore太远,其影响力被PP1等超过,就主要表现为去磷酸化。

    AuroraB+PP1 kinetochore模型

     

    这篇文章在 current biology中还有一篇双飞文章,是从budding yeast角度证实的,那篇文章的模型没有这个的漂亮,所以就不多做介绍了,有兴趣看我对这篇文章的评价

    http://www.xinkexue.com/bib-ref-refid-792.html

    Vanoosthuyse, V., & Hardwick, K. (2009). A Novel Protein Phosphatase 1-Dependent Spindle Checkpoint Silencing Mechanism Current Biology, 19 (14), 1176-1181 DOI: 10.1016/j.cub.2009.05.060

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