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Research Description:
Our research is focused on understanding how cells respond stress. One of our major interests is the mechanism by which cells protect themselves from iron toxicity. Iron is an essential element required by organisms for growth and survival. This is implicit in the role iron plays in many biological processes. Free iron is toxic to cells due to its ability to catalyze the formation of reactive oxygen species. Oxidative stress has been implicated in aging, cancer, ischemia/reperfusion injury and in neurodegenerative disease. To prevent iron mediated-oxidative damage, proteins known as iron-regulatory proteins 1 and 2 (IRPs) control cellular iron levels. IRPs are RNA-binding proteins that bind to a specific stem-loop that is located in the untranslated regions of mRNAs that encode proteins involved in iron and energy homeostasis. The binding of IRPs to RNA regulates the translation or stability of the mRNA. IRP1 and IRP2 are regulated by postranslationally by iron but by different mechanisms: In the presence of high iron, IRP1 forms an [4Fe-4S] cluster and loses affinity for RNA, while IRP2 is rapidly degraded by a specific iron-mediated process. In addition to iron, other stresses regulate IRPs, including hypoxia, and reactive oxygen and nitrogen species. We are interested in determining the signaling pathways that regulate IRPs by iron, hypoxia and oxidative stress, and determining the consequences of this regulation during pathological states, such as ischemia/reperfusion injury and in neurodegeneration.
Research Keywords:
Iron, stress, hypoxia, post-transcriptional regulation, RNA-binding protein, protein degradation