
2004-08 J.H. & E.M. Billings-Bascom Professorship in Nutrition
1999 J.H. & E.M. Billings-Bascom Professorship in Nutrition
1998 Mead Johnson Award, American Institute of Nutrition
- Iron-dependent post transcriptional control of mitochondrial aconitase expression
- Biography of John W Suttie, PhD
- Dysregulation of the sensory and regulatory pathways controlling cellular iron metabolism in unilateral obstructive nephropathy
- Roquin is a major mediator of iron-regulated changes to transferrin receptor-1 mRNA stability
- Differential translational control of 5' IRE-containing mRNA in response to dietary iron deficiency and acute iron overload
- Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation
- A synergistic role of IRP1 and FBXL5 proteins in coordinating iron metabolism during cell proliferation
- Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells
- The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability
- Low intracellular iron increases the stability of matriptase-2
Iron is crucial to cell viability because it is a component of proteins that function in a large number of physiological processes including respiration and cell division. However, excess iron can be toxic because it participates in the production of potentially lethal oxidizing agents. All organisms possess specific iron-binding and other proteins that function in concert to allow cells to make use of the essential properties of iron while minimizing its potentially toxic attributes. Genetic or nutritional perturbations of iron metabolism impair the health of nearly one-third of the world’s population.
Mammalian iron metabolism is modulated through changes in the synthesis of proteins required for the uptake, storage, and use of iron. Synthesis of these proteins is controlled post-transcriptionally by regulatory RNA binding proteins, the iron regulatory proteins (IRPs). Two IRPs, IRP1 and IRP2, exist and each can independently regulate the use of IRE-containing mRNA. Under appropriate conditions IRPs bind stem-loop structures (IREs) in the mRNAs encoding proteins of iron metabolism thereby regulating the translation or stability of the affected mRNA. In this manner iron, and other factors that regulate IRP RNA binding activity, alter the uptake and metabolic fate of iron.
Our efforts are focused on understanding the pathways that lead to regulation of IRP RNA binding activity and the mechanisms through which IRP selectively regulate the translation or stability of various IRE-containing mRNA. For example, IRP1 is a bifunctional protein serving either as a sequence specific RNA binding protein or as the Fe-S enzyme cytosolic aconitase (c-acon) which interconverts citrate and isocitrate. The presence of absence of the Fe-S cluster is an important mechanism for regulating RNA binding by IRP1. We are investigating how phosphorylation by protein kinase C affects iron-regulation of IRP1 by the Fe-S cluster and by iron-induced protein degradation. In addition, we how phosphorylation at a second site selectively regulates the aconitase function of IRP1. We are also interested in determining how IRPs discriminate between their different mRNA targets in order to regulate cellular iron metabolism. Current work in this area focuses on the role of RNA structure and stability of the IRE region as well as the efficiency with which a given mRNA is translated as determinants of the ability of IRP to regulate their translation. In addition, we are investigating the physiological consequences of IRP-dependent regulation of mRNA encoding proteins that are not known to be involved in iron metabolism including the tricarboxylic acid (TCA) cycle enzyme mitochondrial aconitase (m-acon) a protein related to, but different from, c-acon.