HYPOXIC REGULATION OF IRON REGULATORY PROTEIN 2 (IRP2)

低氧(低氧)是正常胚胎发育和血管形成的关键成分，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。无论是在正常情况下还是在病理生理情况下，氧分压的降低都会影响广泛的细胞过程。哺乳动物基因表达模式的重新编程以维持低氧环境的新陈代谢需求是一个普遍存在的事件。这在一定程度上是通过低氧诱导转录因子低氧诱导因子1α(HIF-1α)的激活实现的。在确定HIF-α在低氧中的作用方面做了大量的工作，然而，对转录后调控机制知之甚少。RNA结合铁调节蛋白2(IRP2)是一种重要的转录后调节蛋白，最近发现在低氧条件下通过蛋白质稳定机制进行调节。进一步的研究表明，IRP2蛋白稳定性的调节与HIF-1α惊人地相似。因此，IRP2和HIF-1α的低氧稳定似乎是通过类似的氧感应/信号通路介导的，允许在转录后和转录水平上协调基因表达的调节。由于IRP2是一种铁敏感蛋白，目前参与细胞内的铁稳态，低氧对IRP2的调节可能在铁稳态和氧稳态之间提供了一条通道。此外，与HIF-1α类似，低氧对IRP2的调节在细胞适应环境中可能是重要的。对低氧细胞培养模型的研究为细胞对低氧适应的分子过程提供了有价值的信息。使用这样的模型，这个建议集中在定义缺氧性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的动态平衡的见解；(2)扩大我们对低氧转录后基因调控机制的了解；(3)加深我们对IRP2降解调控机制的理解。

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.