权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The regulation of Wilms' tumour 1 by phospholipid

磷脂对肾母细胞瘤1的调节

基本信息

批准号：
MR/K001027/1
负责人：
Stefan Roberts
金额：
$ 37.82万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK001027%2F1
关键词：
regulation Wilms tumour phospholipid

项目摘要

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.

Wilms'tumor 1蛋白，WT 1，首先在一种影响儿童的肾癌中被发现。WT 1通常在这种类型的癌症中丢失，这表明WT 1通常提供保护。WT 1的相反作用见于许多成人癌症，包括肺癌和乳腺癌。在这里，WT 1有助于推动癌症的形成。因此，WT 1似乎在儿童和成人癌症中具有相反的作用。我们发现了WT 1的一个相互作用伙伴，一种名为BASP 1的蛋白质。BASP 1能够绑定到WT 1并改变WT 1的行为方式。BASP 1是一种与DNA结合的蛋白质，它负责WT 1在癌症的保护或启动之间的功能转换。它与基因的控制区结合并开启它们，当BASP 1与WT 1结合时，这会导致基因关闭。这就是BASP 1如何将WT 1的功能从癌症促进剂改变为癌症预防剂。我们发现BASP 1需要与一种名为PIP 2的小天然化学物质结合。PIP 2是一种脂肪，通常与包围细胞的膜相关。令人惊讶的是，当PIP 2与WT 1和DNA相互作用时，它需要与BASP 1结合。如果没有PIP 2，BASP 1无法与WT 1一起正常工作。我们的工作展示了一种新的基因开关方式，该方案描述了确定PIP 2如何与BASP 1和WT 1一起改变基因开关状态的实验。具体目标有三个：1。我们将确定BASP 1和PIP 2如何导致WT 1开启和关闭基因的能力发生变化。这将涉及到观察基因在细胞内被包裹成束的方式。BASP 1和PIP 2对基因捆绑的影响将决定它们如何与WT 1一起工作以打开和关闭基因。我们将确定BASP 1如何与PIP 2结合，以及这如何改变BASP 1与WT 1结合的方式。将确定与PIP 2结合所需的BASP 1的具体特征。深入了解BASP 1-PIP 2伙伴关系如何根据细胞的状态而变化。WT 1首先被确定为儿童肾癌中功能丧失的因素。我们将使用前两个目标的信息来确定WT 1，BASP 1和PIP 2如何改变通常发育成肾细胞的细胞类型的行为。这将涉及研究它们如何作用，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WT 1在癌症中的关键作用提供新的见解。它们还将为涉及WT 1和BASP 1的癌症的治疗干预开辟新途径。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cholesterol is required for transcriptional repression by BASP1.

DOI：
10.1073/pnas.2101671118
发表时间：
2021-07-20
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Loats AE;Carrera S;Fleming AF;Roberts ARE;Sherrard A;Toska E;Moorhouse AJ;Medler KF;Roberts SGE
通讯作者：
Roberts SGE

Cholesterol is required for transcriptional repression by BASP1

BASP1 的转录抑制需要胆固醇