The ability to sense and respond to changes in environmental and metabolic cues such as oxygen availability is critical for many developmental, physiological and pathophysiological processes including angiogenesis, cerebral and myocardial ischemia and tumorigenesis. In mammalian cells, exposure to a low oxygen environment (hypoxia) triggers an evolutionarily conserved hypoxic response pathway centered on the regulated expression of the hypoxia-inducible transcription factor (HIF). HIF promotes transcription of genes that mediate cellular adaptation to hypoxia through their roles in glycolytic metabolism, cellular proliferation and survival, and oxygen delivery. The stability and activity of HIF are each regulated as a function of oxygen by members of the Iron- and 2-oxoglutarate-dependent dioxygenase family that fill a role as environmental and metabolic sensors, a paradigm that may extend to other biological pathways. Our laboratory is pursuing both (1) the mechanisms of HIF and dioxygenase regulation, and (2) the identification of small molecule agonists and antagonists of the hypoxic response pathway.
Our work on the regulation of dioxygenases by iron availability has led to the initiation of a new area of research in the lab: investigation of cellular pathways mediating cellular iron homeostasis. Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of genes responsible for iron uptake, release, utilization, and storage through the actions of Iron Regulatory Proteins (IRPs). However, the manner in which iron levels are sensed to affect IRP2 activity is poorly understood. We have recently identified an E3 ubiquitin ligase complex that targets IRP2 for proteasomal degradation. The stability of E3 ligase itself is regulated, accumulating under iron and oxygen replete conditions and degraded upon iron depletion. This E3 ligase contains an iron- and oxygen-binding domain that acts as a ligand-binding regulatory switch mediating its differential stability. These observations suggest a mechanistic link between iron- and oxygen-sensing via the E3 ligase, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis and has implications for a number of human diseases including anemia, iron overload disease, neurodegeneration and cancer.
RESEARCH INTERESTS
Regulation of mammalian oxygen homeostasis
Regulation of mammalian iron homeostasis
Cellular sensors of environmental and metabolic cues
Cancer
RECENT PUBLICATIONS
Salahudeen, A.A., Thompson, J.W., Ruiz, J.C., Ma, H., Kinch, L.N., Li, Q., Grishin, N.V, and Bruick, R.K., "An E3 Ligase Possessing an Iron Responsive Hemerythrin Domain is a Regulator of Iron Homeostasis" Science, In press. 2009
Salahudeen, A.S., and Bruick, R.K., "Maintaining Mammalian Iron and Oxygen Homeostasis: Sensors, Regulation, and Crosstalk" Annals of the New York Acad. Sci., In press 2009
Scheuermann, T.H., Tomchick, D.R., Machius, M., Guo, Y., Bruick, R.K., and Gardner, K.H., "Artificial Ligand Binding within the HIF2α PAS-B Domain of the HIF2 Transcription Factor" Proc. Natl. Acad. Sci. USA., 106:450-455, 2009
Nguyen, A.D., McDonald, J.G., Bruick, R.K., and Debose-Boyd, R.A., "Hypoxia Stimulates Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase through Accumulation of Lanosterol and Hypoxia-Inducible Factor-mediated Induction of Insigs" J. Biol. Chem., 282:27436-27446, 2007
Chang, B., Chen, Y., Zhao, Y., and Bruick, R.K., "JMJD6 is a Histone Arginine Demethylase" Science, 318:444-447, 2007
SIGNIFICANT PUBLICATIONS
Salahudeen, A.A., Thompson, J.W., Ruiz, J.C., Ma, H., Kinch, L.N., Li, Q., Grishin, N.V, and Bruick, R.K., "An E3 Ligase Possessing an Iron Responsive Hemerythrin Domain is a Regulator of Iron Homeostasis" Science, In press 2009
Yang, J., Zhang, L., Erbel, P.J.A., Gardner, K.H., Ding, K., Garcia, J.A., and Bruick, R.K., "Functions of the Per/ARNT/Sim (PAS) Domains of the Hypoxia Inducible Factor (HIF)" J. Biol. Chem., 280:36047-36054, 2005
Ozer, A., Wu, L.C., and Bruick R.K., "The candidate tumor suppressor ING4 represses activation of the Hypoxia Inducible Factor (HIF)" Proc. Natl. Acad. Sci. USA., 102:7481-7486, 2005
Peet, D.J., Lando, D., Whelan, D.A., Gorman, J.J., Whitelaw, M.L. and Bruick, R.K., "FIH-1 is an asparaginyl hydroxylase that regulates HIF transcriptional activity" Genes & Dev., 16:1466-1471, 2002
Bruick, R.K. and McKnight, S.L., "A conserved family of prolyl-4-hydroxylases that modify HIF" Science, 294:1337-1340, 2001
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