Fox proteins mediate insulin-increasedPAI-1 transcription

Fox 蛋白介导胰岛素增加的 PAI-1 转录

• 批准号: 7140661
• 负责人: FREDERICK M STANLEY
• 金额: $ 16.5万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140661
• 关键词: cytokine; diabetes mellitus therapy; gene expression; genetic promoter element; genetic transcription; insulin dependent diabetes mellitus; insulin sensitivity /resistance; medical complication; noninsulin dependent diabetes mellitus; oxidative stress; plasminogen activator inhibitors; tissue /cell culture; transcription factor; vascular endothelium

DESCRIPTION (provided by applicant): PAI-1over expression in diabetes may be central to all of the major complications of diabetes; retinopathy, nephropathy, neuropathy, wound healing and macrovascular disease. It is a required component in development, tissue migration, tissue remodeling and cell adhesion as well as being a potent inhibitor of protease activation. Its production is highly disregulated in diabetes due to increased transcription in response to insulin and oxidative stress. It is essential to understand how insulin and oxidative stress activate the PAI-1 promoter and how its activity can be normalized in diabetes. Hyperinsulinemia is one of the key changes in type II diabetes while patients with type I diabetes and treated with insulin are exposed to pharmacological insulin levels. It has recently become appreciated that although cells become resistant to the metabolic effects of insulin, the mitogenic effects of insulin remain insulin responsive. This results in a double defect with glucose transport and metabolism becoming refractory to insulin while transcription of insulin responsive genes is hyperactivated. PAI-1 is one such insulin-activated gene. The PAI-1 promoter is also responsive to oxidative stress that is part of the pathology of diabetes and insulin and oxidative stress combine to produce an additive increase in PAI-1 production. We have defined the insulin response element of the PAI-1 promoter and have determined that the insulin activated transcription factor that activates this element is a Forkhead-related transcription factor. We have also determined that oxidative stress activates an AP-1 response element that is adjacent to the insulin response element. This is accomplished through activation of JNK/SAPK and phosphorylation of c-jun that increases binding of the AP1 complex to the PAI-1 promoter. Insulin and oxidative stress induce an additive activation of transcription. It is important to identify the Forkhead related transcription factor that mediates the insulin response of the promoter and to determine how it is activated by insulin. This proposal sets forth a strategy for accomplishing these goals.

说明（由申请人提供）：糖尿病中派-1的过度表达可能是糖尿病所有主要并发症的核心;视网膜病变、肾病、神经病变、伤口愈合和大血管疾病。它是发育、组织迁移、组织重塑和细胞粘附所需的组分，也是蛋白酶活化的有效抑制剂。由于对胰岛素和氧化应激的反应增加了转录，其产生在糖尿病中高度失调。了解胰岛素和氧化应激如何激活派-1启动子以及其活性如何在糖尿病中正常化至关重要。高胰岛素血症是II型糖尿病的关键变化之一，而接受胰岛素治疗的I型糖尿病患者会暴露于药理学胰岛素水平。最近认识到，尽管细胞变得对胰岛素的代谢作用具有抗性，但胰岛素的促有丝分裂作用仍然是胰岛素响应性的。这导致双重缺陷，葡萄糖转运和代谢变得对胰岛素不敏感，而胰岛素应答基因的转录被过度激活。派-1就是这样一种胰岛素激活基因。派-1启动子还响应于氧化应激，氧化应激是糖尿病病理学的一部分，胰岛素和氧化应激联合收割机产生派-1产生的累加增加。我们已经定义了派-1启动子的胰岛素应答元件，并确定了激活该元件的胰岛素激活转录因子是叉头相关转录因子。我们还确定，氧化应激激活AP-1反应元件，其邻近胰岛素反应元件。这是通过激活JNK/SAPK和磷酸化c-jun来实现的，c-jun增加了AP 1复合物与派-1启动子的结合。胰岛素和氧化应激诱导转录的叠加激活。重要的是要确定叉头相关的转录因子介导的启动子的胰岛素反应，并确定它是如何被胰岛素激活。本提案提出了实现这些目标的战略。