The role of the hCDC14B-HIPK2-MeCP2 axis in mitotic cell fate determination.

hCDC14B-HIPK2-MeCP2 轴在有丝分裂细胞命运决定中的作用。

基本信息

项目摘要

CDC14 is a conserved phosphatase that in the model organism budding yeast has an essential function in the regulation of mitotic exit, the transition from mitosis into G1. Human cells have three CDC14 paralogues of which only hCDC14A and hCDC14B are widely expressed. In the past we have analysed the functions of hCDC14A and hCDC14B and have identified substrates of these phosphatases. hCDC14A is associated with centrosomes and the actin cytoskeleton and we have shown functions in actin organisation and cilia length control. In contrast, hCDC14B associates with the nucleolus during interphase and binds to centrosomes and chromatin in mitosis. Recently, we have identified hCDC14B substrates through phospho-proteome analysis of hCDC14B overexpressing cells. The protein MeCP2 (Methyl CpG binding Protein 2) that binds to tri-methylated histone H3 where it functions as transcriptional repressor was identified as hCDC14B substrate.Analysis of untransformed human RPE1 cells with genomic deletion in hCDC14B revealed that cyclin B1 protein levels (and thereby CDK1-cyclin B1 activity) are increased in these cells, similar to published data from CDC14B KO mouse embryonic fibroblasts. Our data suggest that this increase in cyclin B1 has the consequence that cells with disturbances that affect the mitotic spindle stay longer in mitosis in comparison to hCDC14B wild type cells. Our preliminary data suggest that cyclin B1 is controlled by the antagonistic activities of hCDC14B and the kinase HIPK2 (Homeodomain Interacting Protein Kinase 2) on MeCP2S92. Phosphorylated MeCP2S92 then promotes, probably via translation control, enhanced accumulation of cyclin B1. This model is supported by numerous preliminary data and suggests a novel regulatory mechanism that controls progression through mitosis and cell fate decision (slippage into G1 versus mitotic cell death) in response to mitotic disturbances. Here we will test this model further. We will study how altered hCDC14B levels impact cell fate in response to mitotic disturbances, how this impacts cyclin B1 and finally we will test the notion that the phosphorylation status of MeCP2 as determined by HIPK2 and hCDC14B controls translation of cyclin B1 by an unknown mechanism. The second part is focused on the regulation of HIPK2 in response to mitotic stress, the consequences of HIPK2 modifications, whether the spindle assembly checkpoint regulates HIPK2 and how HIPK2 becomes stabilized under mitotic stress conditions. Together, this project will help us to understand how cells adjust cyclin B1 levels in response to mitotic disturbances and how this impacts cell fate decision. Since mitotic slippage into G1 is accompanied with the formation of tetraploid cells that are an intermediate state in neoplastic transformation, this proposal will help understanding the mechanistic principals of this deleterious step and how it can be prevented.
CDC 14是一种保守的磷酸酶,在模式生物芽殖酵母中,它在有丝分裂退出(从有丝分裂到G1期的转变)的调节中具有重要功能。人类细胞具有三种CDC 14旁系同源物,其中仅hCDC 14 A和hCDC 14 B广泛表达。在过去,我们分析了hCDC 14 A和hCDC 14 B的功能,并确定了这些磷酸酶的底物。hCDC 14 A与中心体和肌动蛋白细胞骨架相关,我们已经显示了在肌动蛋白组织和纤毛长度控制中的功能。相比之下,hCDC 14 B在间期与核仁结合,并在有丝分裂中与中心体和染色质结合。最近,我们通过对hCDC 14 B过表达细胞的磷酸化蛋白质组学分析鉴定了hCDC 14 B底物。与三甲基化组蛋白H3结合的蛋白MeCP 2(甲基CpG结合蛋白2)在其作为转录阻遏物起作用时被鉴定为hCDC 14 B底物。对hCDC 14 B中基因组缺失的未转化的人RPE 1细胞的分析显示,在这些细胞中细胞周期蛋白B1蛋白水平(以及由此CDK 1-细胞周期蛋白B1活性)增加,类似于来自CDC 14 B KO小鼠胚胎成纤维细胞的已发表数据。我们的数据表明,细胞周期蛋白B1的这种增加的结果是,与hCDC 14 B野生型细胞相比,具有影响有丝分裂纺锤体的干扰的细胞在有丝分裂中停留更长时间。我们的初步数据表明,细胞周期蛋白B1是由hCDC 14 B和激酶HIPK 2(同源结构域相互作用蛋白激酶2)对MeCP 2S 92的拮抗活性控制的。磷酸化的MeCP 2S 92可能通过翻译控制促进细胞周期蛋白B1的积累。该模型得到了许多初步数据的支持,并提出了一种新的调控机制,该机制通过有丝分裂和细胞命运决定(滑入G1期与有丝分裂细胞死亡)来控制有丝分裂障碍的进展。在这里,我们将进一步测试这个模型。我们将研究hCDC 14 B水平的改变如何影响细胞命运以响应有丝分裂紊乱,这如何影响细胞周期蛋白B1,最后我们将测试由HIPK 2和hCDC 14 B确定的MeCP 2的磷酸化状态通过未知机制控制细胞周期蛋白B1的翻译的概念。第二部分重点介绍了HIPK 2在有丝分裂应激中的调节,HIPK 2修饰的后果,纺锤体组装检查点是否调节HIPK 2以及HIPK 2在有丝分裂应激条件下如何变得稳定。总之,这个项目将帮助我们了解细胞如何调整细胞周期蛋白B1水平,以应对有丝分裂干扰,以及这如何影响细胞命运的决定。由于有丝分裂滑入G1伴随着四倍体细胞的形成,这是肿瘤转化的中间状态,这一建议将有助于理解这一有害步骤的机械原理以及如何预防。

项目成果

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Professor Dr. Elmar Schiebel其他文献

Professor Dr. Elmar Schiebel的其他文献

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{{ truncateString('Professor Dr. Elmar Schiebel', 18)}}的其他基金

Insertion of the nuclear pore complex and the yeast spindle pole body into the nuclear envelope.
将核孔复合体和酵母纺锤体极体插入核膜中。
  • 批准号:
    202157009
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Grants
DBT-DFG Indo-German Research Proposal: The recruitment of the γ-TuRC to the Sas-6 cartwheel for centriole microtubule assembly
DBT-DFG 印度-德国研究提案:将 γ-TuRC 募集到 Sas-6 侧手翻以进行中心粒微管组装
  • 批准号:
    465380792
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Spatial organisation of centrosomes by centrosome cohesion and centrosome nuclear envelope interactions.
通过中心体内聚力和中心体核膜相互作用进行中心体的空间组织。
  • 批准号:
    298572189
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

相似海外基金

Release of hCdc14B phosphatase from the nucleolus in response to DNA damage (04)
DNA 损伤时核仁释放 hCdc14B 磷酸酶 (04)
  • 批准号:
    224652078
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Collaborative Research Centres
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