HYPOXIC REGULATION OF IRON REGULATORY PROTEIN 2 (IRP2)

缺氧（氧气减少）是正常胚胎发育和血管形成的重要组成部分，也是红细胞生成的主要刺激因素。此外，缺氧与心血管疾病、脑缺血和肿瘤进展有关。无论从正常或病理生理的情况下，氧张力的降低影响了广泛的细胞过程。哺乳动物基因表达模式的重编程以维持缺氧环境的代谢需要是一个普遍存在的事件。这部分是通过缺氧诱导的转录因子缺氧诱导因子-1 α (HIF-1 α)的激活来实现的。在确定hif - α在缺氧中的作用方面已经付出了很多努力，然而，对转录后调节机制的了解相对较少。RNA结合铁调节蛋白2 （RNA binding iron regulatory protein 2, IRP2）是一种重要的转录后调节因子，最近发现它通过一种涉及蛋白质稳定的机制受到缺氧的调节。进一步的研究表明，IRP2蛋白稳定性的调控与HIF- 1alpha惊人的相似。因此，IRP2和HIF- 1alpha的缺氧稳定似乎是通过类似的氧传感/信号通路介导的，从而允许在转录后和转录水平上协调调节基因表达。由于IRP2是一种铁敏感蛋白，目前参与细胞铁稳态，其受缺氧的调节可能在铁稳态和氧稳态之间提供了一个通道。此外，与HIF-1alpha类似，缺氧对IRP2的调节可能在细胞适应环境中起重要作用。缺氧细胞培养模型的研究为细胞适应缺氧的分子过程提供了有价值的信息。使用这样的模型，本建议的重点是定义缺氧IRP2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)扩大我们对缺氧转录后基因调控机制的认识；(3)进一步了解调控IRP2降解的机制。

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.