HYPOXIC REGULATION OF IRON REGULATORY PROTEIN 2 (IRP2)

铁调节蛋白 2 (IRP2) 的缺氧调节

• 批准号: 6231307
• 负责人: ERIC S HANSON
• 金额: $ 9.34万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6231307
• 关键词: RNA binding protein; hypoxia; immunoprecipitation; oxidation; phosphorylation; protein degradation; tissue /cell culture; ubiquitin

Hypoxia (decreased oxygen) is a critical component of normal embryonic development and vascularization, and is the primary stimulus for erythropoiesis. Furthermore, hypoxia is associated with cardiovascular disease, cerebral ischemia, and tumor progression. Whether from normal or pathophysiological situations, a decrease in oxygen tension affects a wide range of cellular processes. The reprogramming of mammalian gene expression patterns to sustain the metabolic needs of a hypoxic environment is a ubiquitous event. This is achieved, in part, by hypoxia- induced activation of the transcription factor termed hypoxia inducible factor-1 alpha (HIF-1 alpha). Much effort has gone into determining the role of HIF-alpha during hypoxia, however, comparatively little is known about post-transcriptional regulatory mechanisms. The RNA binding iron regulatory protein 2 (IRP2), an important post-transcriptional regulator, was recently found to be regulates by hypoxia by a mechanism involving protein stabilization. Further studies have demonstrated that the regulation of IRP2 protein stability is strikingly similar to that of HIF- 1alpha. It appears, therefore, that hypoxic stabilization of IRP2 and HIF- 1alpha is mediated through a similar oxygen sensing/signaling pathway, allowing for the coordinated regulation of gene expression at the post - transcriptional and transcriptional levels. Since IRP2 is an iron sensing protein that is current involved in cellular iron homeostasis, its regulation by hypoxia may provide a conduit between iron homeostasis and oxygen homeostasis. Further, similar to HIF-1alpha, IRP2 regulation by hypoxia may be important in cellular adaptation environment. Studies with cell culture models of hypoxia have provided valuable information on the molecular processes underlying cellular adaptation to hypoxia. Using such a model, this proposal is focused on defining the mechanics of hypoxic IRP2 stabilization. The results from these studies will: (1) provide insights as to how cells coordinate iron and oxygen homeostasis; (2) extent our knowledge on the mechanisms of hypoxic post-transcriptional gene regulation; and (3) further our understanding of the mechanisms regulating IRP2 degradation.

缺氧（氧气减少）是正常胚胎发育和血管形成的关键组成部分，也是红细胞生成的主要刺激因素。此外，缺氧与心血管疾病、脑缺血和肿瘤进展相关。无论是从正常或病理生理的情况下，在氧张力的降低影响范围广泛的细胞过程。哺乳动物基因表达模式的重编程以维持低氧环境的代谢需要是普遍存在的事件。这部分是通过缺氧诱导的转录因子（称为缺氧诱导因子-1 α（HIF-1 α））的激活来实现的.许多努力已经确定HIF-α在缺氧过程中的作用，然而，对转录后调控机制知之甚少。RNA结合铁调节蛋白2（IRP 2）是一种重要的转录后调节因子，近年来发现其受缺氧的调节，其调节机制涉及蛋白质稳定化。进一步的研究表明，IRP 2蛋白稳定性的调节与HIF-1 α的调节惊人地相似。因此，似乎IRP 2和HIF-1 α的低氧稳定是通过类似的氧传感/信号传导途径介导的，从而允许在转录后和转录水平协调调节基因表达。由于IRP 2是一种铁敏感蛋白，目前参与细胞铁稳态，其调节缺氧可能提供了铁稳态和氧稳态之间的管道。此外，与HIF-1 α类似，缺氧对IRP 2的调节在细胞适应环境中可能是重要的。缺氧的细胞培养模型的研究提供了有价值的信息，细胞适应缺氧的分子过程。使用这样的模型，该建议的重点是定义缺氧IRP 2稳定的机制。这些研究的结果将：（1）提供关于细胞如何协调铁和氧稳态的见解;（2）扩展我们对缺氧转录后基因调控机制的知识;（3）进一步了解调节IRP 2降解的机制。