The ability to sense and respond to changes in 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 Fe(II)- 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 (1) mechanisms of HIF and dioxygenase regulation, (2) the identification of small molecule agonists and antagonists of the hypoxic response pathway, and (3) studies aimed at exploring the biological roles of other candidate Fe(II)- and 2-oxoglutarate-dependent dioxygenases.
RESEARCH INTERESTS
Cellular oxygen sensing
Regulation of the mammalian hypoxic response pathway
tumorigenesis
ischemia
RECENT PUBLICATIONS
Bingsheng Chang, Yue Chen, Yingming Zhao, Richard K. Bruick, "JMJD6 is a Histone Arginine Demethylase" Science, 318:444-447, October 2007
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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