Mylab defines and
characterizes the mechanisms animals use to detect and respond to
stress. I currently study these processes in the free-living nematode Caenorhabditis
elegans using a variety of physiological, genetic, molecular,
and biochemical approaches. Environmental stress strongly influences
physiological and biochemical adaptations in animals and contributes to
and age-related diseases in humans.
Project 1. Cytoprotective gene
genes protect animals from stress and stress-related diseases such as
neurodegeneration, and inflammation. The molecular details of how
cytoprotective gene expression is regulated by stress and coordinated
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
genes that promote stress resistance and longevity. SKN-1 is regulated
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
problem, I recently used RNA interference and a transgenic fluorescent
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
functions to regulate SKN-1 protein stability downstream from
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
other novel regulators identified in the screen. The functions of SKN-1
highly conserved with the homologous mammalian transcription factor
plays a central role in preventing cancer, neurodegeneration, and
in healthy cells and promoting multidrug resistance in tumor cells.
these studies may provide fundamental insights into how animal cells
topical and clinically relevant family of transcription factors.
Project 2. Understanding and
targeting multidrug resistance in nematodes
parasitize ~25% of humans and cause debilitating and potentially fatal
diseases. Helminth targeting drugs, or anthelmintics, have been used to
parasitic nematodes for decades. However, many parasitic nematodes are
resistance. Multidrug resistant strains are especially problematic
are insensitive to all current anthelmintics. In systems ranging from
to cancer cells, multidrug resistance is mediated by increased
activity of cytoprotective enzymes that detoxify xenobiotics. The
molecular and genetic mechanisms of multidrug resistance are poorly
nematodes because parasitic species are difficult to culture and study
experimentally. My lab will use
elegans as a model nematode to identify genes that are
exposure to antihelmintics and to define pathways that mediate
resistance. We will also build on my recent findings (see above) to
characterize the role of SKN-1 and WDR-23 in mediating multidrug
A major obstacle to
studying and targeting multidrug resistance in parasitic nematodes is
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
because they simultaneously regulate multiple detoxification genes. The
size, simple culturing characteristics, and genetic tractability of C.
elegans make it an ideal system in which to discover,
optimize inhibitors of SKN-1. These compounds would provide much needed
for studying multidrug resistance and could eventually be used to
useful life of current and future anthelmintics improving the lives of
of millions of people.
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.