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

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在一起。然而，一种特殊的细胞死亡形式，称为细胞凋亡，在我们的胚胎发育过程中是非常正常的部分，在此期间，多余的、不需要的细胞会以一种谨慎控制的方式被移除。例如，当我们在子宫中时，形成指间网状结构的细胞通过细胞凋亡被移除。细胞凋亡对于移除病变或受损的细胞也很重要，例如那些具有潜在致癌基因突变的细胞。事实上，去除受损细胞的过程中的缺陷可能会导致癌症和自身免疫的发展。细胞的命运，无论是死亡还是死亡，都取决于细胞内支持死亡和支持生存的蛋白质的微妙平衡。如果支持生存的蛋白质积累过多，那么细胞就会积累，导致发育异常或癌症。如果促死亡蛋白积累，那么太多的细胞死亡，这会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，支持死亡或支持生存的蛋白质的丰富程度代表着一个关键的控制点。其中一种名为Bim的致死蛋白似乎相对重要，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)，可能会患上某种形式的白血病，这是一种血细胞癌。在这两种情况下，这都是因为细胞没有在应该死亡的时候死亡。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在Bim蛋白上附加特定的信号或“旗帜”来修改它，从而指导它进行破坏。通过这种方式，Bim蛋白质被分解成其组成的氨基酸，以便循环使用，从而保护细胞免受死亡。在这项提议中，我们想要了解Bim蛋白被‘标记’为破坏的机制。一种特定的酶可以将一种名为泛素的小分子的几个拷贝连接到Bim上；这种泛素分子起到了‘旗帜’的作用，指导Bim蛋白质的破坏，保护细胞免受死亡。我们想要确定负责将泛素标记附着到BIM上的酶，原因有两个。首先，因为它本身就很有趣，因为它将教会我们很多关于“正常”细胞死亡是如何被控制的。其次，由于Bim是一种重要的致死分子，负责破坏Bim的酶可能会导致癌症或自身免疫，因此可能会教会我们更多关于这些疾病的知识。

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.