The regulation of Wilms' tumour 1 by phospholipid

Wilms的肿瘤蛋白WT1最初是在一种影响儿童的肾癌中发现的。WT1通常在这种类型的癌症中丢失，这表明WT1通常提供保护。在包括肺癌和乳腺癌在内的许多成人癌症中，WT1的作用正好相反。在这里，WT1帮助驱动癌症的形成。因此，WT1在儿童和成人癌症中似乎具有相反的作用。我们发现了WT1的一个相互作用伙伴，一个名为BASP1的蛋白质。BASP1能够与WT1结合并改变WT1的行为方式。BASP1负责将WT1的功能转换为癌症的保护器或启动器。WT1是一种与DNA结合的蛋白质。它与基因的控制区域结合并开启它们。当BASP1与WT1结合时，会导致基因关闭。这就是BASP1如何改变WT1从癌症启动子到癌症预防者的功能。我们发现BASP1需要与一种叫做PIP2的天然化学物质结合。PIP2是一种脂肪，通常与细胞周围的膜有关。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， BASP1就不能与WT1一起正常工作。我们的工作展示了一种开启和关闭基因的新方法。本提案描述了确定PIP2如何与BASP1和WT1一起作用以改变基因的开关状态的实验。有三个具体目标；我们将确定BASP1和PIP2如何引起WT1开关基因开启和关闭能力的变化。这将包括研究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结合，以及这如何改变BASP1与WT1结合的方式。将确定BASP1与PIP2结合所需的具体特征。我们将深入了解BASP1-PIP2伙伴关系是如何根据细胞状态而变化的。WT1首先被确定为儿童肾癌中丧失功能的一个因素。我们将使用来自前两个目标的信息来确定WT1， BASP1和PIP2如何改变通常发育为肾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类似癌症的方式生长，而不是形成专门的肾细胞。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。它们还将为涉及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.