Fox proteins mediate insulin-increasedPAI-1 transcription

描述(申请人提供)：PAI-1在糖尿病中的过度表达可能是糖尿病所有主要并发症的核心，如视网膜病变、肾病、神经病变、伤口愈合和大血管疾病。它是发育、组织迁移、组织重塑和细胞黏附所必需的成分，也是一种有效的蛋白酶激活抑制物。它的产生在糖尿病中高度失调，这是由于胰岛素和氧化应激导致转录增加。了解胰岛素和氧化应激是如何激活PAI-1启动子的，以及如何在糖尿病中使其活性正常化是至关重要的。高胰岛素血症是II型糖尿病的关键变化之一，而I型糖尿病和胰岛素治疗的患者暴露在药物胰岛素水平下。最近人们认识到，尽管细胞对胰岛素的代谢作用产生抵抗，但胰岛素的促有丝分裂作用仍然是对胰岛素的反应。这导致了双重缺陷，葡萄糖的运输和代谢对胰岛素不起作用，同时胰岛素反应基因的转录被过度激活。PAI-1就是这样一种胰岛素激活基因。PAI-1启动子对氧化应激也有反应，氧化应激是糖尿病的一部分，胰岛素和氧化应激结合在一起会导致PAI-1产量的增加。我们已经定义了PAI-1启动子的胰岛素反应元件，并确定了激活该元件的胰岛素激活的转录因子是一个叉头相关的转录因子。我们还确定了氧化应激激活了与胰岛素反应元件相邻的AP-1反应元件。这是通过激活JNK/SAPK和c-Jun的磷酸化来实现的，从而增加了AP1复合体与PAI-1启动子的结合。胰岛素和氧化应激诱导转录的相加激活。重要的是确定介导启动子胰岛素反应的叉头相关转录因子，并确定它是如何被胰岛素激活的。该提案提出了实现这些目标的战略。

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.