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，在此期间，多余的，不需要的细胞以一种精心控制的方式被去除。例如，当我们在子宫中时，形成我们手指之间的蹼的细胞通过凋亡而被去除。细胞凋亡对于去除患病或受损的细胞也很重要，例如具有潜在致癌基因突变的细胞。事实上，在去除受损细胞的过程中存在缺陷可能会导致癌症和自身免疫的发展。细胞的命运，无论是死亡还是不死亡，都是由细胞内促死亡和促存活蛋白质的精细平衡决定的。如果促生存蛋白积累过量，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，这可能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，大量的促死亡或促生存蛋白代表了一个关键的控制点。其中一种名为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），并且可以发展某种形式的白血病，这是一种血细胞癌症。在这两种情况下，这都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累。特别是，细胞内的生存信号通过将特定信号或“标志”附着到Bim蛋白上来修改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回收，并保护细胞免于死亡。在这个提议中，我们想了解Bim蛋白被“标记”破坏的机制。一种特殊的酶允许将一种称为泛素的小分子的几个拷贝附着到Bim上;这种泛素分子充当“旗帜”，指导Bim蛋白破坏并保护细胞免于死亡。我们想确定负责将泛素标记附着到Bim的酶，原因有二。首先，因为它本身就很有趣，因为它会教我们很多关于“正常”细胞死亡是如何控制的。其次，由于Bim是一种重要的促死亡分子，负责标记Bim以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。

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.