HYPOXIC REGULATION OF IRON REGULATORY PROTEIN 2 (IRP2)

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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.