Phosphoregulation of Mitochondrial Survivin in Cancer Cells

癌细胞中线粒体生存素的磷酸调节

基本信息

  • 批准号:
    1804162
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Studentship
  • 财政年份:
    2016
  • 资助国家:
    英国
  • 起止时间:
    2016 至 无数据
  • 项目状态:
    已结题

项目摘要

The Wheatley lab has been working for over a decade on the cancer-associated protein survivin. This fascinating little protein is essential for mitosis and cell division, but also prevents cells from dying (1,2). It is overexpressed in all cancers and its abundance correlates with poor patient prognosis, resistance to conventional chemotherapy and radiation, and metastasis.Phosphotidylethanolamine (PE) is a phospholipid that is critical to membrane architecture: it facilitates positive curvature by virtue of its small head group. Consequently PE exposure at the plasma membrane (PM) of the cleavage furrow is critical for completion of cell division, and its high expression in mitochondrial cristae governs mitochondrial integrity, ultimately impacting on the metabolic needs of the cell, and cellular response to apoptotic stimuli (3). PE is also a critical regulator of autophagy, the recycling pathway initiated by cells during stressful conditions (4). At its outset autophagy is a pro-survival mechanism, but if it continues unabated, it ultimately causes cell death. In animal cells 80% of the de novo pool of PE is synthesised in the mitochondria by decarboxylating phosphatidylserine (PS), which is imported from the endoplasmic reticulum. Conversion of PS to PE is mediated by the inner mitochondrial membrane resident, phosphatidylserine decarboxylase (PSD), and if PSD is depleted, the PS/PE ratio rises, mitochondrial morphology becomes perturbed, with growth rate, metabolism and apoptosis affected (3).Recently we discovered that survivin interacts directly with PSD in the mitochondria of cancer cells (5). Our initial data suggest that it is a negative regulator of PE production, and we hypothesise that survivin alters membrane architecture by limiting PE availability. In this manner survivin expression can influence many fundamental processes, including cell divisio, mitochondrial health, metabolic reprogamming, and may be able to prevent cells from dying through excessive autophagy. This novel molecular insight suggests that the apparently mutliple and disparate roles of survivin, may be fundamentally linked at this protein-lipid interface. This hypothesis opens up a completely new perspective on survivin function and how it contributes to cancer and other metabolic disorders.In this project, the regulation of survivin-PSD interaction by phosphorylation (cdk1/p38) will be investigated. In preliminary work we have mapped the interaction between survivin and PSD to the baculovirus inhibitor of apoptosis repeat (BIR) domain of survivin and the decarboxylase domain of PSD (5). Within the BIR domain there is a unique cdk1 site (T34), and previous work from our lab has shown that cells expressing T34 mutants, grow slowly, are highly resistant to apoptosis and are insentive to irradiation (6). Moreover, by electron microscopy we have discovered that mitochondrial integrity is compromised in these cells. Thus the goal of this project is to investigate the impact cdk1/p38 phosphorylation of T34 on survivin-PSD interaction, PE production and to document the downstream consequences in terms of cell division, metabolism, response to apoptotic stimuli including radiation, and excessive autophagy.
惠特利实验室十多年来一直致力于研究癌症相关蛋白生存素。这种迷人的小蛋白质是必不可少的有丝分裂和细胞分裂,但也防止细胞死亡(1,2)。磷脂酰乙醇胺(PE)是一种磷脂,对细胞膜结构至关重要:它的头部基团较小,有利于细胞膜的正曲率。因此,在卵裂沟的质膜(PM)处的PE暴露对于完成细胞分裂至关重要,并且其在线粒体嵴中的高表达控制线粒体完整性,最终影响细胞的代谢需求和细胞对凋亡刺激的反应(3)。PE也是自噬的关键调节剂,自噬是细胞在应激条件下启动的再循环途径(4)。自噬一开始是一种促生存机制,但如果它继续不减,它最终会导致细胞死亡。在动物细胞中,80%的PE从头池在线粒体中通过脱羧磷脂酰丝氨酸(PS)合成,PS从内质网输入。PS向PE的转化由线粒体内膜驻留的磷脂酰丝氨酸脱羧酶(PSD)介导,并且如果PSD耗尽,则PS/PE比率上升,线粒体形态变得紊乱,生长速率、代谢和凋亡受到影响(3)。最近我们发现存活素在癌细胞的线粒体中与PSD直接相互作用(5)。我们的初步数据表明,它是一个负调节PE生产,我们假设,生存素改变膜结构,通过限制PE的可用性。以这种方式,生存素表达可以影响许多基本过程,包括细胞分裂、线粒体健康、代谢再结合,并且可能能够防止细胞通过过度自噬而死亡。这一新的分子见解表明,生存素的明显多重和不同的作用,可能是从根本上联系在这个蛋白质-脂质界面。这一假说为研究survivin的功能及其与癌症和其他代谢紊乱的关系开辟了一个全新的视角。本项目将研究磷酸化(cdk 1/p38)对survivin与PSD相互作用的调控。在初步工作中,我们已经将存活素和PSD之间的相互作用定位于存活素的凋亡重复的杆状病毒抑制剂(BIR)结构域和PSD的脱羧酶结构域(5)。在BIR结构域中有一个独特的cdk 1位点(T34),我们实验室以前的工作表明,表达T34突变体的细胞生长缓慢,对细胞凋亡具有高度抗性,对辐射不敏感(6)。此外,通过电子显微镜,我们发现这些细胞中线粒体的完整性受到损害。因此,本项目的目标是研究T34的cdk 1/p38磷酸化对存活素-PSD相互作用、PE产生的影响,并记录细胞分裂、代谢、对凋亡刺激(包括辐射)的反应和过度自噬的下游后果。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A cost-effective, analytical method for measuring metabolic load of mitochondria.
  • DOI:
    10.1016/j.metop.2019.100020
  • 发表时间:
    2019-12-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Grey, James F E;Townley, Amelia R;Wheatley, Sally P
  • 通讯作者:
    Wheatley, Sally P
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其他文献

吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
  • DOI:
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  • 影响因子:
    0
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LiDAR Implementations for Autonomous Vehicle Applications
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
生命分子工学・海洋生命工学研究室
生物分子工程/海洋生物技术实验室
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
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  • 通讯作者:
Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
  • DOI:
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    0
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的其他文献

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{{ truncateString('', 18)}}的其他基金

An implantable biosensor microsystem for real-time measurement of circulating biomarkers
用于实时测量循环生物标志物的植入式生物传感器微系统
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    2901954
  • 财政年份:
    2028
  • 资助金额:
    --
  • 项目类别:
    Studentship
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利用人类肠道微生物群的多糖分解能力来开发环境可持续的洗碗解决方案
  • 批准号:
    2896097
  • 财政年份:
    2027
  • 资助金额:
    --
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    Studentship
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可以在颗粒材料中游动的机器人
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    --
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    2027
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质子、α 和 γ 辐照辅助应力腐蚀开裂:了解燃料-不锈钢界面
  • 批准号:
    2908693
  • 财政年份:
    2027
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    --
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    Studentship
Field Assisted Sintering of Nuclear Fuel Simulants
核燃料模拟物的现场辅助烧结
  • 批准号:
    2908917
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
    Studentship
Assessment of new fatigue capable titanium alloys for aerospace applications
评估用于航空航天应用的新型抗疲劳钛合金
  • 批准号:
    2879438
  • 财政年份:
    2027
  • 资助金额:
    --
  • 项目类别:
    Studentship
Developing a 3D printed skin model using a Dextran - Collagen hydrogel to analyse the cellular and epigenetic effects of interleukin-17 inhibitors in
使用右旋糖酐-胶原蛋白水凝胶开发 3D 打印皮肤模型,以分析白细胞介素 17 抑制剂的细胞和表观遗传效应
  • 批准号:
    2890513
  • 财政年份:
    2027
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  • 项目类别:
    Studentship
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CDT 第 1 年,预计 2024 年 10 月
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