How does ERK1/2-dependent phosphorylation target BimEL to the proteasome?

ERK1/2 依赖性磷酸化如何将 BimEL 靶向蛋白酶体？

• 批准号: BB/E02162X/1
• 负责人: Simon Cook
• 金额: $ 45.22万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE02162X%2F1
• 关键词: How; does; ERK1; dependent; phosphorylation

The death of a cell sounds like a rather catastrophic event and so is perhaps most easily associated with disease. However, a special form of cell death, called apoptosis, is a perfectly normal part of our embryological development during which excess, unwanted cells are removed in a carefully controlled fashion. For example, the cells that form the webs between our fingers when we are in the womb are removed by apoptosis. Apoptosis is also important for the removal of diseased or damaged cells such as those with potentially cancer-causing gene mutations. Indeed, defects in this process of removing damaged cells can contribute to the development of cancer and auto-immunity. The fate of a cell, whether to die or not, is determined by the fine balance of pro-death and pro-survival proteins inside the cell. If pro-survival proteins accumulate to excess then cells can accumulate, resulting in developmental abnormalities or cancer. If pro-death proteins accumulate then too many cells die and this can again cause problems during development but can also contribute to diseases such as Alzheimer's dementia. These studies tell us that the abundance of pro-death or pro-survival proteins represents a key point of control. One such pro-death protein, called Bim, appears to be relatively important because genetically engineered mice that lack Bim have a hyper-active immune system (similar to auto-immunity) and can develop some forms of leukaemia, a type of a cancer of the blood cells. In both cases this is because cells don't die when they should do. The abundance of the Bim protein is an important point of control and there are mechanisms in place to make sure that Bim does not accumulate at the wrong time or place. In particular, survival signals inside the cell modify the Bim protein by attaching specific signals or 'flags' to it, thereby directing it for destruction. In this way the Bim protein is broken down into its constituent amino acids for recycling and the cell is protected from death. In this proposal, we want to understand the mechanism by which the Bim protein is 'flagged' for destruction. A specific enzyme allows the attachment of several copies of a small molecule called ubiquitin to Bim; this ubiquitin molecule acts as the 'flag', directing the Bim protein for destruction and protecting the cell from death. We want to identify the enzyme responsible for attachment of the ubiquitin flags to Bim for two reasons. First, because it is interesting in its own right as it will teach us much about how 'normal' cell death is controlled. Second, because Bim is an important pro-death molecule, the enzyme responsible for flagging Bim for destruction may contribute to cancer or auto-immunity, and so may teach us more about these diseases.

一个细胞的死亡听起来像是一个相当灾难性的事件，因此可能最容易与疾病联系起来。然而，一种特殊形式的细胞死亡，称为细胞凋亡，是我们胚胎发育的一个完全正常的部分，在这个过程中，多余的、不需要的细胞以一种精心控制的方式被移除。例如，当我们还在子宫里的时候，形成手指间蛛网的细胞就会因细胞凋亡而消失。细胞凋亡对于去除病变或受损细胞（如那些具有潜在致癌基因突变的细胞）也很重要。事实上，在清除受损细胞的过程中出现的缺陷会导致癌症和自身免疫的发展。细胞的命运，是否死亡，是由细胞内促死亡和促生存蛋白质的微妙平衡决定的。如果促生存蛋白积累过量，细胞也会积累，导致发育异常或癌症。如果促死蛋白积累，那么太多的细胞就会死亡，这可能再次导致发育过程中的问题，但也可能导致阿尔茨海默氏症等疾病。这些研究告诉我们，促死亡或促生存蛋白的丰度是一个关键的控制点。其中一种被称为Bim的促死亡蛋白似乎相对重要，因为缺乏Bim的基因工程小鼠具有高度活跃的免疫系统（类似于自身免疫），并可能发展成某些形式的白血病，这是一种血细胞癌症。在这两种情况下，这是因为细胞在应该死亡的时候没有死亡。Bim蛋白的丰度是一个重要的控制点，并且有适当的机制来确保Bim不会在错误的时间或地点积聚。特别是，细胞内的生存信号通过附加特定的信号或“标志”来修饰Bim蛋白，从而指导其破坏。通过这种方式，Bim蛋白被分解成其组成氨基酸进行循环利用，从而保护细胞免于死亡。在这个提议中，我们想要了解Bim蛋白被“标记”为破坏的机制。一种特殊的酶可以让一种叫做泛素的小分子的几个拷贝附着在Bim上；这种泛素分子充当“旗帜”，指导Bim蛋白的破坏，保护细胞免于死亡。出于两个原因，我们想要确定负责将泛素标记附着到Bim上的酶。首先，因为它本身就很有趣，因为它将告诉我们很多关于“正常”细胞死亡是如何控制的。其次，因为Bim是一种重要的促死亡分子，负责标记Bim进行破坏的酶可能会导致癌症或自身免疫，因此可能会让我们更多地了解这些疾病。

项目成果

Granulocyte/macrophage colony-stimulating factor causes a paradoxical increase in the BH3-only pro-apoptotic protein Bim in human neutrophils.

粒细胞/巨噬细胞集落刺激因子导致人中性粒细胞中仅 BH3 的促凋亡蛋白 Bim 反常增加。

• DOI: 10.1165/rcmb.2010-0101oc
• 发表时间: 2011-06
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Cowburn AS;Summers C;Dunmore BJ;Farahi N;Hayhoe RP;Print CG;Cook SJ;Chilvers ER
• 通讯作者: Chilvers ER

Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling.

通过ERK1/2 MAP激酶信号传导控制细胞死亡和线粒体裂变。

• DOI: 10.1111/febs.14122
• 发表时间: 2017-12
• 期刊: The FEBS journal
• 作者: Cook SJ;Stuart K;Gilley R;Sale MJ
• 通讯作者: Sale MJ

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.

• DOI: 10.1371/journal.pone.0184907
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Darling NJ;Balmanno K;Cook SJ
• 通讯作者: Cook SJ

The BH3 mimetic ABT-263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance.

BH3 模拟物 ABT-263 与 MEK1/2 抑制剂 selumetinib/AZD6244 协同作用，促进 BIM 依赖性肿瘤细胞死亡并抑制获得性耐药。

• DOI: 10.1042/bj20121212
• 发表时间: 2013
• 期刊: The Biochemical journal
• 作者: Sale MJ