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Kyung S. Lee, Ph.D.

Portait Photo of Kyung Lee
Laboratory of Metabolism
Head, Chemistry Section
Senior Investigator
Center for Cancer Research
National Cancer Institute
Building 37, Room 3122C
Bethesda, MD 20892
Phone:  
301-496-9635
Fax:  
301-496-8419
E-Mail:  
kyunglee@mail.nih.gov

Biography

Dr. Kyung Lee received his Ph.D. in 1994 from the Department of Biochemistry at the Johns Hopkins University in Baltimore. He then worked with Raymond Erikson at Harvard University as a postdoctoral fellow and studied in the fields of protein kinase and cancer. In 1998, he joined NIH as a tenure-track investigator in the Laboratory of Metabolism at NCI. In 2005, Dr. Lee became a senior investigator and head of the Chemistry Section in Laboratory of Metabolism.

Dr. Lee is the recipient of an NCI Intramural Research Award, a Society for Biomedical Research CKD Award, and several Federal Technology Transfer Awards for his inventions and patents related to Plk1. He serves as an academic editor for PLoS ONE.

Research

The polo subfamily of the Ser/Thr protein kinases plays pivotal roles in cell proliferation. Among the four polo-like kinases (Plk1–4; collectively, Plks) found in mammalian cells, Plk1 has drawn much attention because of its tight association with neoplastic transformation of human cells. Plk1 regulates diverse biochemical and cellular events at multiple stages of M phase, including centrosome maturation, bipolar spindle formation, DNA damage adaptation, mitotic entry, anaphase-promoting complex activation, and cytokinesis. Our group demonstrated that the polo-box domain (PBD) present in the C-terminal non-catalytic region of Plk1 is essentially required for proper localization of Plk1 to distinct subcellular locations. PBD specifically interacts with phospho-S/T-containing epitopes generated by either Plk1 itself (self-priming) or Cdc2 or other Pro-directed kinases (nonself-priming), consequently bringing the N-terminal Plk1 catalytic domain in close proximity to its physiological substrates. These findings demonstrate that PBD-dependent interaction constitutes the biochemical basis of Plk1-dependent cellular processes. Intriguingly, Plk1 is several-fold overexpressed in a wide spectrum of human cancers and an elevated level of Plk1 activity is required for the viability of cancer cells but not normal cells. Therefore, we hypothesize that isolating novel PBD-binding proteins selectively enriched in cancer cells and investigating the nature of the PBD-dependent interaction with these targets are critical for better understanding the mechanism of how Plk1-dependent processes are rewired in human cancers and how these altered interactions contribute to tumorigenesis.

As a part of our initial effort to steer a drug discovery program aimed at fulfilling the NCI's mission to combat cancer, we have taken the unique approach of targeting the non-catalytic, but functionally essential, PBD of Plk1. By exploring the high-affinity interaction between Plk1 PBD and the kinetochore protein PBIP1/CENP-U, we discovered a 5-amino acid-long phosphopeptide, PLHSpT (Kd ~450 nM), whose phosphomimetic form effectively blocks the function of Plk1 in HeLa cells. Conjugation of an alkylphenyl moiety to the His residue resulted in approximately three orders of magnitude increased activity against Plk1 PBD (Kd ~1 nM) without compromising its specificity. Further development of derivatives containing monoanionic pThr esters that exhibit an increased cellular activity is underway. In a separate approach, we carried out a high-throughput screening of ~500,000 small molecules and isolated several promising hits. Characterization of these hits, combined with structure-based drug design and delivery, are the areas of interest that we plan to further explore.

To extend our understanding of the role of PBD in mediating Plks-dependent processes, we have investigated how the poorly characterized cryptic polo-box (CPB) of Plk4 functions. Plk4 is a key regulator of centriole duplication, an event critical for the maintenance of genomic integrity. Our results demonstrated that Plk4 itself is regulated in time and space through sequential interactions with two distinct scaffolds, Cep192 and Cep152, and this intricate process is centrally required to promote Plk4-mediated centriole biogenesis and to prevent aneuploidy, which can lead to cancer in humans. Interestingly, unlike the PBDs of Plk1-3, the CPB of Plk4 forms a stable dimer and interacts with Cep192 and Cep152 in a phospho-independent manner. Since Plk4 is considered to be a candidate anticancer target, further investigation into the molecular basis of how CPB interacts with its binding targets will likely be important for the development of novel anticancer therapeutics against Plk4.

This page was last updated on 6/30/2014.