ANTIAPOPTOTIC FUNCTION OF THE INSULIN RECEPTOR

工作总结：细胞凋亡是一种自然现象 在细胞的正常周转中起主要作用的现象。在……里面 近年来，越来越多的证据表明，胰岛素具有 抗凋亡特性，部分是通过激活转录因子 已知的参与控制细胞凋亡的分子 进程。利用不同胰岛素受体基因转染的细胞 突变体，我们确定了胰岛素所起的重要作用 受体激酶功能，但观察到酪氨酸磷酸化 胰岛素受体底物-1(IRS-1)和随后的 磷脂酰肌醇3‘-激酶的激活不参与 胰岛素受体的存活特性。但是我们发现， RAS相关小GTP结合蛋白的法尼化可能是 参与胰岛素的抗细胞凋亡保护作用。在同一项下 实验条件下，GLP-1受体的触发也 提供对细胞凋亡性死亡的抵抗。蛋白质是否 法尼化是GLP-1作用中的一个必要步骤，目前尚不清楚。这个 李权S博士工作的重要性通过接待 1998年格伦基金会内分泌学和老年学奖。这个 这些研究的结果现已发表在《生物化学》杂志上。确实有 目前已知的RAS家族中只有三个成员 法尼化并以质膜为靶点。我们目前正在 确定这三个成员中是否有任何一个扮演着至关重要的角色 在胰岛素抗细胞凋亡信号转导中的作用。 野生型和显性负性突变体对细胞的影响 这些小的GTP结合蛋白的研究正在进行中。因为 RAS超家族的一些成员和它们之间的相互作用 Raf-1丝氨酸/苏氨酸激酶代表一种受调控的整合型 酪氨酸激酶受体-和环之间的串行点 AMP依赖的信号级联，我们计划研究其作用 胰岛素和GLP-1对Raf-1激活的影响，这可能是 在几种细胞类型中存活。人们普遍认为， 糖尿病的破坏性并发症是长期的结果 高血糖时期。也是细胞呼吸的副产品 因为在糖尿病条件下发现的高血糖浓度可以 导致细胞死亡。我们计划通过以下方式来描述这一机制 哪种葡萄糖及其代谢物起促进因子的作用 在某些组织中发生细胞凋亡，而在其他组织中则不发生。

Summary of work: Apoptosis is a natural phenomenon that plays a major role in normal turnover of cells. In recent years, evidence accumulated to indicate that insulin has antiapoptotic properties, in part, by activating transcription factors that are known to be involved in the control of the apoptotic process. Using cells transfected with various insulin receptor mutants, we established the important role played by the insulin receptor kinase function but observed that tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and the subsequent activation of phosphatidylinositol 3'-kinase do not contribute to the survival properties of the insulin receptor. However, we found that farnesylation of Ras-related small GTP-binding proteins may be involved in the antiapoptotic protection by insulin. Under the same experimental conditions, triggering of the GLP-1 receptor also confers resistance against apoptotic death. Whether protein farnesylation is a required step in GLP-1 action is unclear. The importance of Dr. Lee-Kwon?s work was highlighted by receiving the 1998 Glenn Foundation Endocrinology and Aging Award. The results of these studies are now in press in Biochemistry. There are only three members of the Ras family that are known to be farnesylated and targeted at the plasma membrane. We are currently establishing whether any of these three members play an essential role in the transduction of the insulin's antiapoptotic signals. Transfection of cells with wild-type and dominant-negative mutant of these small GTP-binding proteins is underway. Because the interaction between some members of the Ras superfamily and Raf-1 serine/threonine kinase represents a regulated integrative point for cross talk between tyrosine kinase receptor- and cyclic AMP-dependent signaling cascades, we plan to investigate the role of insulin and GLP-1 on Raf-1 activation, a possible trigger for survival in several cell types. It is widely believed that the devastating complications of diabetes are the results of prolonged periods of hyperglycemia. Byproducts of cellular respiration as well as high glucose concentrations found in diabetic conditions can result in cell death. We plan to characterize the mechanism by which glucose and its metabolites functions as a progression factor for apoptosis in some tissues but not in others.