Antagonism of PI 3-kinase signalling by PTEN and SHIP2

PTEN 和 SHIP2 拮抗 PI 3 激酶信号传导

• 批准号: G0801865/1
• 负责人: Charles Downes
• 金额: $ 217.51万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801865%2F1
• 关键词: Antagonism; PI; kinase; signalling; PTEN

The human body is made up of cells which form the tissues and organs. The different tissues of the body have developed to perform specialised functions which must be coordinated for the organism as a whole to function efficiently and survive. Cell signalling is the process by which cells in our bodies communicate with one another and signal transduction is the means by which a specific signal (perhaps a hormone, such as insulin), arriving at its target tissue, is interpreted to elicit a particular response. Defects in cell signalling are common causes of important human diseases such as cancer and diabetes. We are studying the details of a signal transduction process which malfunctions in more than 50% of human tumours and which accounts for many of the effects of insulin produced after a meal. The central character of this response is a fatty substance or lipid called PIP3 which is made by enzymes called PI 3-kinases. When this substance is produced at the correct time, in the right part of the cell and in small, but sufficient amounts it triggers normal cell responses, but too much, in the wrong place or at an inappropriate time can lead to or promote the development of a tumour. On the other hand, producing too little in response to insulin can be a cause of diabetes. Maintaining this delicate balance of PIP3 involves the PI 3-kinase enzymes which make PIP3 and enzymes called phosphatases which remove it. We are studying the factors which regulate two classes of PIP3 phosphatase called PTEN and SHIP2. PTEN is a tumour suppressor that is mutated or absent in many different kinds of human tumour. We use tissue culture cells to study PTEN and SHIP2 regulation and epithelial cells (the source of most solid tumours) as simple models of disease to examine the consequences of defects in PIP3 phosphatase activity. Lastly, we are developing unique mouse models harbouring specific defects in the PTEN gene to validate the physiological significance of our work using cultured cells. Because of its importance in human disease many pharmaceutical companies are developing drugs which block the PI 3-kinase signalling pathway including inhibitors, currently in clinical trials as anti-cancer or anti-inflammatory agents, of PI 3-kinases themselves. My group has a longstanding, active collaboration with a consortium of 5 international companies to accelerate their drug discovery endeavours in this field.

人体是由组成组织和器官的细胞组成的。身体的不同组织已经发展到执行专门的功能，必须协调有机体作为一个整体有效地运作和生存。细胞信号传导是我们体内细胞相互沟通的过程，信号转导是指特定信号（可能是激素，如胰岛素）到达目标组织后被解释为引发特定反应的手段。细胞信号传导缺陷是癌症和糖尿病等重要人类疾病的常见原因。我们正在研究信号转导过程的细节，该过程在超过50%的人类肿瘤中出现故障，并解释了餐后产生的胰岛素的许多影响。这种反应的中心特征是一种叫做PIP3的脂肪物质或脂质，它是由一种叫做PIP3激酶的酶产生的。当这种物质在正确的时间，在细胞的正确部位，以少量但足够的量产生时，它会触发正常的细胞反应，但在错误的地方或不适当的时间，过量的这种物质会导致或促进肿瘤的发展。另一方面，对胰岛素的反应太少可能是糖尿病的一个原因。维持PIP3的这种微妙平衡涉及到制造PIP3的pi3激酶和去除PIP3的磷酸酶。我们正在研究调节两类PIP3磷酸酶PTEN和SHIP2的因子。PTEN是一种肿瘤抑制因子，在许多不同种类的人类肿瘤中发生突变或缺失。我们使用组织培养细胞来研究PTEN和SHIP2的调控，并将上皮细胞（大多数实体瘤的来源）作为简单的疾病模型来检查PIP3磷酸酶活性缺陷的后果。最后，我们正在开发独特的小鼠模型，其中包含PTEN基因中的特定缺陷，以验证我们使用培养细胞的工作的生理意义。由于PI - 3激酶在人类疾病中的重要性，许多制药公司正在开发阻断PI - 3激酶信号通路的药物，包括PI - 3激酶本身的抑制剂，目前在临床试验中用作抗癌或抗炎剂。我的小组与5家国际公司组成的联盟长期积极合作，以加速它们在这一领域的药物发现工作。