The regulation of Wilms' tumour 1 by phospholipid

Wilms家族的肿瘤1蛋白WT1首次在一种影响儿童的肾癌中被发现。WT1在这种类型的癌症中通常缺失，这表明WT1通常提供保护。WT1的相反作用在许多成人癌症中都可以看到，包括肺癌和乳腺癌。在这里，WT1有助于推动癌症的形成。因此，WT1似乎在儿童和成人癌症中具有相反的作用。我们发现了WT1的相互作用伙伴，一种名为BASP1的蛋白质。BASP1能够绑定到WT1并改变WT1的行为方式。BASP1负责将WT1的功能在癌症的保护者或促进者之间切换。WT1是一种与DNA结合的蛋白质。它结合到基因的控制区，并开启它们。当BASP1与WT1结合时，这会导致基因关闭。这就是BASP1如何将WT1的功能从癌症促进者改变为癌症防御者。我们发现BASP1需要与一种名为PIP2的小型天然化学物质结合。PIP2是一种脂肪，通常与细胞周围的细胞膜有关。令人惊讶的是，当PIP2与WT1和DNA相互作用时，它需要与BASP1结合。如果没有PIP2，则BASP1无法与WT1一起正常工作。我们的工作展示了一种新的开关基因的方法。这项提议描述了确定PIP2如何与BASP1和WT1一起发挥作用来改变基因的开关状态的实验。有三个具体的目标：1.我们将确定BASP1和PIP2如何导致WT1打开和关闭基因的能力的变化。这将涉及到观察基因在细胞内包裹成束的方式。BASP1和PIP2对基因捆绑的影响将决定它们如何与WT1一起开启和关闭基因。我们将确定BASP1如何与PIP2绑定，以及这如何改变BASP1与WT1的绑定方式。将确定与PIP2结合所需的BASP1的特定功能。将获得对BASP1-PIP2伙伴关系如何根据细胞状态而变化的见解。WT1首次被确定为儿童肾癌功能丧失的一个因素。我们将使用来自前两个目标的信息来确定WT1、BASP1和PIP2如何改变正常发育为肾脏细胞的细胞类型的行为。这将包括观察它们如何使细胞继续以癌症的方式生长，而不是形成特殊的肾脏细胞。这些研究的完成将为WT1在癌症中的关键作用提供新的见解。他们还将为涉及WT1和BASP1的癌症的治疗干预开辟新的途径。

The Wilms' tumour 1 protein, WT1, was first identified in a type of kidney cancer that affects children. WT1 is generally lost in this type of cancer, which suggests that WT1 normally offers protection. An opposite role for WT1 is seen in many adult cancers, including of the lung and breast. Here, WT1 helps to drive formation of the cancer. Thus, WT1 appears to have opposite effects in childhood and adult cancers. We have discovered an interaction partner of WT1, a protein named BASP1. BASP1 is able to bind to WT1 and change the way that WT1 behaves. BASP1 is responsible for switching the function of WT1 between a protector or a promoter of cancer.WT1 is a protein that binds to DNA. It binds to the control regions of genes and switches them on. When BASP1 binds to WT1, this causes genes to switch off instead. This is how BASP1 changes the function of WT1 from a cancer-promoter to a cancer-preventer. We have found that BASP1 needs to bind to a small natural chemical called PIP2. PIP2 is a type of fat that is normally associated with the membrane that surrounds cells. Surprisingly, PIP2 needs to bind to BASP1 when it interacts with WT1 and DNA. Without PIP2, BASP1 does not function correctly with WT1. Our work has demonstrated a new way for switching genes on and off.This proposal describes experiments to determine how PIP2 functions with BASP1 and WT1 to change the on-off status of genes. There are three specific aims;1. We will determine how BASP1 and PIP2 cause changes in the ability of WT1 to switch genes on and off. This will involve looking at the way that genes are wrapped into bundles inside the cell. The effect of BASP1 and PIP2 on the bundling of genes will determine how they work with WT1 to switch genes on and off.2. We will determine how BASP1 binds to PIP2 and how this changes the way that BASP1 binds to WT1. The specific features of BASP1 that are needed for binding to PIP2 will be determined. Insights into how the BASP1-PIP2 partnership changes depending upon the state of the cell will be obtained.3. WT1 was first identified as a factor that loses function in children's kidney cancer. We will use the information from the first two aims to determine how WT1, BASP1 and PIP2 change the behavior of a cell type that normally develops into a kidney cell. This will involve looking at how they act to make the cells continue to grow in a cancer-like fashion instead of forming specialised kidney cells. The completion of these studies will provide new insights into the critical roles of WT1 in cancer. They will also open new avenues for therapeutic intervention in cancers that involve WT1 and BASP1.