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Betty Leibold

Professor of Medicine and of Oncological Sciences

B.A. State University of New York

Ph.D. Massachusetts Institute of Technology

Research

References

betty.leibold@hmbg.utah.edu

 

Research

We are interested in how eukaryotic cells sense and respond to changes in cellular iron concentration. Iron is essential because it is required for critical metabolic processes, including DNA synthesis, electron transport, oxygen transport and heme synthesis. But iron can also be toxic due to its ability to catalyze the formation of free radicals that damage macromolecules. Excess iron can result in neurodegeneration, cardiomyopathy, cirrhosis and increased risk of cancer while iron deficiency perinatally or postnatally can result in neurocognitive impairments in children. Because of the deleterious yet beneficial effects of iron, highly regulated mechanisms are used to sense, acquire and store this metal.

Iron regulatory proteins (IRPs) 1 and 2 are key regulators of iron homeostasis in mammalian cells. IRPs are cytosolic proteins that bind to RNA stem-loop structures known as iron-responsive elements (IREs) that are located in the untranslated regions of mRNAs encoding proteins involved in iron and energy homeostasis, and in cell cycle regulation. The binding of IRPs to target IRE-mRNAs regulates the translation or the stability of mRNAs. Increased cellular iron causes IRP1 to form a [4Fe-4S] cluster and lose RNA-binding activity while iron causes IRP2 to be rapidly degraded by the proteasome. Our research is focused in four areas.

Mechanisms of IRP2 iron and oxygen sensing. One major question is how IRP2 senses and responds to changes in cellular iron concentration. IRP2 is specifically targeted for degradation when iron levels rise, allowing for the post-transcriptional regulation of IRE-target mRNAs whose expression is required for adaptation to iron. We are interested in identifying the components of the IRP2 iron-sensing machinery. IRP1 and IRP2 are also regulated by oxidative stress and hypoxia (low oxygen). Hypoxia is important for normal physiology, as well as being a component of pathophysiological conditions, including heart disease and tumor growth. We are studying how cellular redox alters IRP activity and the physiological consequences of this regulation. We use mammalian cell culture and biochemical approaches to study mechanisms of IRP regulation.

Regulation of iron homeostasis during proliferation. Iron is essential for proliferation and differentiation of cells due to its role in DNA synthesis and energy production. Because the cellular response to iron depletion is G1/S cell cycle arrest, iron chelators are used clinically as anti-proliferative agents. We have identified a phosphorylation site in IRP2 that alters its activity during the cell cycle, which provides evidence for a functional connection between iron homeostasis and the cell cycle. We are examining how IRP2 phosphorylation affects cell cycle progression and its role in the proliferation of cancer cells.

Iron and disease. The ability of iron to catalyze free radicals requires that the concentration of iron must be maintained within defined limits to prevent iron damage. Consequently, both iron overload and deficiency can result in disease. Deletion of IRP2 in mice leads to anemia, neurodegeneration and metabolic defects. Our studies are aimed at determining the molecular mechanisms by which IRP2 deficiency leads to these physiological abnormalities.

Caenorhabditis elegans as a genetic model for iron homeostasis. We are using C. elegans as a model organism to identify novel iron-regulated genes and pathways in worms that have similar roles in mammals. We are studying the molecular mechanisms by which iron coordinately regulates the activation or repression of genes controlling the uptake, storage and utilization of iron. Biochemical approaches and genetic screens are being employed to identify components involved in this process..

References