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Keith P. Choe

Assistant Professor
Ph.D. University of Florida, 2005

321 Bartram Hall
Personal Website

Research Interests

Mylab defines and characterizes the mechanisms animals use to detect and respond to environmental stress. I currently study these processes in the free-living nematode Caenorhabditis elegans using a variety of physiological, genetic, molecular, cell biology, and biochemical approaches. Environmental stress strongly influences physiological and biochemical adaptations in animals and contributes to aging and age-related diseases in humans.

Project 1. Cytoprotective gene expression

Cytoprotective genes protect animals from stress and stress-related diseases such as cancer, neurodegeneration, and inflammation. The molecular details of how cytoprotective gene expression is regulated by stress and coordinated with other processes are poorly defined. The nematode C. elegans provides numerous experimental advantages for defining these processes, which include a sequenced and well-annotated genome, genetic tractability, and simple manipulation of gene expression. In C. elegans, the transcription factor SKN-1 regulates multiple cytoprotective genes that promote stress resistance and longevity. SKN-1 is regulated by multiple protein kinase pathways that respond to stress, metabolic, and developmental signals, but the mechanisms of activation and signal integration are not known. To begin solving this problem, I recently used RNA interference and a transgenic fluorescent reporter of SKN-1 activity to perform a genome-wide screen for regulators of cytoprotective gene expression. Detailed analysis of a subset of regulatory genes defined a new pathway in which a novel WD40 repeat protein named WDR-23 functions to regulate SKN-1 protein stability downstream from previously identified protein kinase pathways. My lab will build on these findings to define how WDR-23, SKN-1, and upstream kinases interact to integrate diverse signals. My lab will also begin to define the role of 22 other novel regulators identified in the screen. The functions of SKN-1 are highly conserved with the homologous mammalian transcription factor Nrf2, which plays a central role in preventing cancer, neurodegeneration, and inflammation in healthy cells and promoting multidrug resistance in tumor cells. Therefore, these studies may provide fundamental insights into how animal cells regulate a topical and clinically relevant family of transcription factors.

Project 2. Understanding and targeting multidrug resistance in nematodes

Nematodes parasitize ~25% of humans and cause debilitating and potentially fatal diseases. Helminth targeting drugs, or anthelmintics, have been used to control parasitic nematodes for decades. However, many parasitic nematodes are evolving resistance. Multidrug resistant strains are especially problematic because they are insensitive to all current anthelmintics. In systems ranging from microbes to cancer cells, multidrug resistance is mediated by increased expression and activity of cytoprotective enzymes that detoxify xenobiotics. The specific molecular and genetic mechanisms of multidrug resistance are poorly defined for nematodes because parasitic species are difficult to culture and study experimentally. My lab will use C. elegans as a model nematode to identify genes that are regulated by exposure to antihelmintics and to define pathways that mediate multidrug resistance. We will also build on my recent findings (see above) to characterize the role of SKN-1 and WDR-23 in mediating multidrug resistance.

A major obstacle to studying and targeting multidrug resistance in parasitic nematodes is the lack of specific probes. My lab will use C. elegans to screen for and develop pharmacological compounds that block the expression of xenobiotic detoxification genes. Transcription factors such as SKN-1 are promising targets because they simultaneously regulate multiple detoxification genes. The small size, simple culturing characteristics, and genetic tractability of C. elegans make it an ideal system in which to discover, characterize, and optimize inhibitors of SKN-1. These compounds would provide much needed tools for studying multidrug resistance and could eventually be used to increase the useful life of current and future anthelmintics improving the lives of hundreds of millions of people.

Representative Publications

PubMed Search for Keith Choe

Choe KP, Leung CK, and Miyamoto MM (in press) Unique structure and regulation of the nematode detoxification gene regulator SKN-1: implications to understanding and controlling drug resistance. Drug Metabolism Reviews

Leung CK, Empinado H, and Choe KP (2012) Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf /SKN-1 and p53/CEP-1. Free Radical Biology and Medicine 52(5):937-950

Leung CK, Deonarine A, Strange K, and Choe KP (2011) High-Throughput screening and biosensing with fluorescent C. elegans strains. Journal of Visualized Experiments 51:2745

Przybysz AJ, Choe KP, Roberts LJ, and Strange K (2009) Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone. Mechanisms of Ageing and Development 130:357-369

Choe KP, Przybysz AJ, and Strange K (2009) The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans. Molecular and Cellular Biology 29:2704-2715

Choe, K. P. and K. Strange (2008) Genome-wide RNAi screen and in vivo protein aggregation reporters identify degradation of damaged proteins as an essential hypertonic stress response. Am J Physiol Cell Physiol 295(6): C1488-1498.

Choe, K. P. and K. Strange (2007) Evolutionarily conserved WNK and Ste20 kinases are essential for acute volume recovery and survival after hypertonic shrinkage in Caenorhabditis elegans. Am J Physiol Cell Physiol 293(3): C915-927.

Choe, K. P. and K. Strange (2007) Molecular and genetic characterization of osmosensing and signal transduction in the nematode Caenorhabditis elegans. FEBS Journal 274(22): 5782-5789.

Choe, K. P., A. Kato, S. Hirose, C. Plata, A. Sindic, M. F. Romero, J. B. Claiborne and D. H. Evans (2005) NHE3 in an ancestral vertebrate: primary sequence, distribution, localization, and function in gills. Am J Physiol Regul Integr Comp Physiol 289: R1520-R1534.

Current Graduate Students

NameEmailResearch Interest
Pauline Fontaine pfontaine@ufl.eduAnimal Biology
Lanlan Tang lanlantang@ufl.eduStress biology and aging

Current Postdocs and Visitors

NameEmailResearch Interest
Ying Wang yingwang@ufl.eduBehavior biology and molecular biology