Randall Wharton King
Our goal is to develop new approaches for treating human disease, based on our understanding of fundamental cell biological principles. We start by identifying new compounds that perturb complex cellular pathways, and then use the compounds as tools to understand the regulation of the pathway. Through this process, we identify new potential drug targets, and illuminate new aspects of cellular regulation.
Our work focuses on understanding cell division, and the regulation of the ubiquitin-proteasome pathway. Several steps in cell division are regulated by ubiquitin-dependent proteolysis. The transition from metaphase to anaphase is initiated by the degradation of proteins that regulate chromosome cohesion, and the exit from mitosis is dependent on the degradation of mitotic cyclins. These proteins are marked for degradation by a multisubunit ubiqitin-protein ligase called the Anaphase Promoting Complex or Cyclosome (APC/C). Through high-throughput screens performed in Xenopus extracts (Verma et al., 2004) our laboratory has identified chemicals that inhibit ubiquitin-dependent degradation by binding the ubiquitin chain (Verma et al., 2004) and more recently compounds that inhibit APC activation by perturbing activator protein binding (Zeng et al., 2010) We are using these small molecules to study the mechanism of APC/C-dependent ubiquitination, and we are exploring the use of these inhibitors as novel anti-cancer agents.
In collaboration with the Finley lab at HMS, we have characterized the role of the proteasome-associated deubiquitinating enzyme Usp14 (Lee et al., 2010). We have recently identified a selective small molecule inhibitor of Usp14 that can enhance the cell's ability to eliminate potentially neurotoxic or damaged proteins (Lee et al., 2010). These findings may provide a new method for treatment of diseases associated with protein misfolding, such as neurodegenerative diseases.
We are also interested in development of new high-throughput technologies for identification of potential drug targets, and have interests in RNAi technologies (Sigoillot and King, 2011) and long-term time lapse imaging.
Institute of Chemistry and Cell Biology
C2-666A, 250 Longwood Ave.
Boston, MA 02115