Kyung Lee, Ph.D.

Center for Cancer Research, National Cancer Institute, National Institutes of Health

kl119z@nih.gov

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 cellular proliferation and mitotic controls. 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, Laboratory of Metabolism, NCI, NIH.

Research Program:

The general research theme of the Chemistry Section is to understand the mechanisms that regulate various mitotic events and cellular proliferation. Our primary focus is to understand the function of mammalian polo-like kinase 1 (Plk1), a critical mitotic kinase that is upregulated in ~ 80% of human cancers. A growing body of evidence suggests that Plk1 plays a critical role in numerous mitotic events and cellular proliferation. As such, down-regulation of Plk1 activity results in mitotic catastrophe and apoptotic cell death, whereas constitutive expression of Plk1 induces oncogenic focus formation and tumors in nude mice. Plk1 has been suggested as a biomarker for several types of human cancers (breast, ovarian, non-small cell lung, head/neck, colon, endometrial and esophageal carcinomas, and leukemias) and is considered an important potential target for anti-cancer therapy. To steer a drug discovery program based on strong basic science and to fulfill the mission of the NCI in eliminating suffering and death from cancer, we are investigating the mechanisms of how Plk1 deregulation leads to the development of cancers in humans. To this end, we have focused on isolating novel Plk1 substrates and binding proteins, two of which have been identified as a kinetochore protein, PBIP1, and a centrosomal protein, hCenexin1. Both of these proteins interact with the polo-box domain (PBD) of Plk1, which is essential for targeting the catalytic activity of Plk1 to specific subcellular structures. The physiological significance of these interactions is currently under investigation. Intriguing early results indicate that Plk1-dependent PBIP1 phosphorylation at T78 induces a high affinity interaction between PBIP1 and Plk1 PBD and as a result p-T78 PBIP1-dependent Plk1 recruitment to the mitotic kinetochores. Absence of the PBIP1-Plk1 interaction leads to chromosome missegregation and aneuploidy, suggesting that PBIP1-dependent Plk1 recruitment to the kinetochores is critical for maintaining chromosome stability. Paradoxically, fully activated Plk1 induces PBIP1 degradation in early mitosis, although the mechanism and the significance of this event are yet to be investigated. Intriguingly, a phospho-T78 peptide specifically bound to Plk1, but not to the related Plk2 or Plk3. Further investigation on the nature of the p-T78 peptide-Plk1 PBD interaction will be important to define the structural determinants for the PBD binding, leading to the isolation and design of anti-Plk1 PBD inhibitors and anti-Plk1 therapeutic agents.

picture of Plk1 localization during mitosis

A model illustrating the self-regulatory mechanism of PBIP1-dependent Plk1 localization and the role of Plk1 in spindle assembly checkpoint. Early in the cell cycle, PBIP1 accumulates at the interphase centromeres prior to Plk1 expression. PBIP1 is also phosphorylated to multiple tiers even before the appearance of Plk1. As Plk1 becomes abundant in G2, Plk1 interacts with PBIP1 and phosphorylates T78 to create a self-docking site for the PBD. This step is critical to promote its own recruitment to the kinetochores. In early mitosis, Plk1 degrades PBIP1 in a manner that is not understood at present. As the level of PBIP1 diminishes, Plk1 is liberated from the PBIP1 tether, and the resulting, free, Plk1 population phosphorylates 3F3/2 and other substrates critical for proper Mad2 recruitment.

movie which shows si-PBIP1 cells exhibiting aberrant chromosome segregation in the presence of misaligned chromosomes52.6Mb AVI Movie
movie which shows apoptosis after a prolonged mitotic arrest66.5Mb AVI Movie

Movies for si-PBIP1 cells. HeLa cells expressing EGFP-histone H2B were cultured on a 35 mm dish on the stage of the Olympus FluoView 1000 confocal system with SIM scanner and inverted microscope equipped with an environmental chamber providing temperature, humidity and CO2 control. Time-lapse images were captured with the FluoView 1000 software every 2 minutes using a spectral detector with BP505-530 nm after excitation with the 488 nm line of an Argon laser. Because of different z positions between interphase and mitotic cells, image capture was started soon after cells enter mitosis (t = 0 min). Unlike control cells (not shown), si-PBIP1 cells exhibited aberrant chromosome segregation in the presence of misaligned chromosomes (A), or apoptosis after a prolonged mitotic arrest (B).

Publications:

National Library of Medicine On-Line Publication List (with abstracts)

  1. Kang, Y.-H., J.-E. Park, L.-R. Yu, N.-K. Soung, S.-M. Yun, J.K. Bang, Y.-S. Seong, H. Yu, S. Garfield, T.D. Veenstra, and K. S. Lee, 2006. Down-regulation of a novel kinetochore-associated mitotic inhibitor PBIP1 by mammalian polo kinase Plk1 is required for the onset of anaphase. Molecular Cell. 24:409-22.
  2. Soung, N. K., Y. H. Kang, K. Kim, K. Kamijo, H. Yoon, Y.-S. Seong, Y. -L. Kuo, T. Miki, S. R. Kim, R. Kuriyama, C. -Z. Giam, C. H. Ahn, and K. S. Lee. 2006. Requirement of hCenexin for proper mitotic functions of polo-like kinase 1 at the centrosomes. Mol. Cell. Biol. 26:8316-35.
  3. Asano, S., J.-E. Park, L.-R. Yu, K. Sakchaisri, C. J. Park, Y. H. Kang, J. Thorner, T. D. Veenstra, K. S. Lee. 2006. Direct phosphorylation and activation of a Nim1-related kinase Gin4 by Elm1 in budding yeast. J. Biol. Chem. 281:27090-27098.
  4. Niiya, F., T. Tatsumoto, K. S. Lee, and T. Miki. 2006. Phosphorylation of the cytokinesis regulator Ect2 by Cdk1 stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA. Oncogene 25:827-837.
  5. Hara, T., M. Abe, H. Inoue, Y. -H. Kang, K. S. Lee, and T. Miki. 2006. Phosphorylation at Threonine341 of Ect2 by Cdk1 releases Ect2 from auto-inhibition. Oncogene 25:566-578.
  6. Lee, K.S., S. Asano, J.-E. Park, K. Sakchaisri, and R.L. Erikson. 2005. Monitoring the cell cycle by multi-kinase-dependent regulation of Swe1/Wee1 in budding yeast. Invited commentary. Cell Cycle 4:1346-1349.
  7. Asano, S., J.-E. Park, K. Sakchaisri, L.-R. Yu, S. Song, P. Supavilai, T. D. Veenstra, K. S. Lee. 2005. Concerted mechanism of Swe1/Wee1 regulation by multiple mitotic kinases in budding yeast. EMBO J. May 26, 2005 24:2194-2204.
  8. Lee, K. S., J. E. Park, S. Asano, C. J. Park. 2005. Yeast polo-like kinases: Functionally conserved multi-task mitotic regulators. Invited review. Oncogene 24:217-229.
  9. Park, J.-E., K. Sakchaisri, C. J. Park, K. Sakchaisri, T. Karpova, S. Asano, J. McNally, Y. Sunwoo, S.-H. Leem, and K. S. Lee. 2004. Dissection of the localization-specific mitotic functions of Cdc5p in S. cerevisiae. Mol. Cell. Biol. 24:9873-9886.
  10. Park, C. J., S. Song, Y. S. Seong, K. Sakchaisri, J. E. Park, H. Ro, M. Winey, and K. S. Lee. 2004. Requirement of Bbp1p, a novel SPB component, for normal mitotic functions of the budding yeast polo kinase, Cdc5p. Mol. Biol. Cell. 15:1711-1723.
  11. Sakchaisri, K., S. Asano, L.-R. Yu, M. J. Shulewitz, C. J. Park, J.-E. Park, T. D. Veenstra, J. Thorner, and K. S. Lee. 2004. Coupling morphogenesis to mitotic entry. Proc. Natl. Acad. Sci. USA. 101: 4124-4129.
  12. Yeon-Sun Seong, Changhee Min, Luowei Li, Jae Young Yang, Soo-Yeon Kim, Xiaodong Cao, Keetae Kim, Stuart H. Yuspa, Hyun-Ho Chung, and Kyung S. Lee. 2003. Characterization of a novel Cdk1 inhibitor, BMI-1026. Cancer Research 63: 7384-7391.
  13. Park, C.J., S. Song, P.R. Lee, W. Shou, R. Deshaies, and K.S. Lee. 2003 Loss of CDC5 function in S. cerevisiae leads to defects in Swe1 regulation and Bfa1/Bub2-independent cytokinesis. Genetics 163:21-33.
  14. Prymakowska-Bosak, M., R. Hock, F. Catez, J.-H. Lim, Y. Birger, H. Shirakawa, K.S. Lee and M. Bustin. 2002. Mitotic phosphorylation of HMGN chromosomal proteins inhibits their nuclear import and promotes interaction with 14.3.3 proteins. Mol. Cell. Biol. 22:6809-6819.
  15. Lee, P.R., S. Song, H. Ro, C.J. Park, J. Lippincott, R. Li, J.R. Pringle, C. De Virgilio, M. Longtine, and K.S. Lee. 2002. Bni5p, a septin-interacting protein, is required for normal septin function and cytokinesis in S. cerevisiae. Mol. Cell. Biol. 22:6906-6920.
  16. Seong, Y.S., J.S. Lee, S.E. Fernandez, R. Kuriyama, T. Miki, and K.S. Lee. 2002. A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of Plk1 in U-2 OS Cells. J. Biol. Chem. 277:32282-32293.
  17. Sobering, A,. W.S. Jung, K.S. Lee, and D.E. Levin. 2002. Yeast Rpi1 is a transcriptional regulator that contributes to preparation for stationary phase. Eukaryotic Cell.1:56-65.
  18. Ro, H., S. Song, and K.S. Lee. 2002. Bfa1 can regulate Tem1 function independently of Bub2 in the mitotic exit network of S. cerevisiae. Proc. Natl. Acad. Sci. USA. 99:5436-5441.
  19. Song, S., and K.S. Lee. 2001. A novel function of Saccharomyces cerevisiae CDC5 in cytokinesis. J. Cell Biol. 152:451-470.
  20. Lee, K.S., and S. Song. 2000. Review article. Cytokinesis: An old story with new challengers in the cell cycle control. Korean Society of Medical Biochemistry and Molecular Biology News 7:15-19.
  21. Elizondo, G., P. Fernandez-Salguero, M.S. Sheikh, G.Y. Kim, A. J. Fornace, K.S.Lee, and F.J. Gonzalez. 2000. Altered cell cycle control at the G2/M phases in aryl hydrocarbon receptor-null embryo fibroblast. Mol. Pharmacol. 57:1056-1063.
  22. Song, S., T.Z. Grenfell, S. Garfield, and K.S. Lee. 2000. Essential Function of the Polo-Box of Cdc5 in Subcellular Localization and Induction of Cytokinetic Structures. Mol. Cell. Biol. 20:286-298.
  23. Lee, K.S., S. Song, and R.L. Erikson. 1999. The Polo-Box-dependent Induction of Ectopic Septal Structures by a Mammalian Polo Kinase, Plk, in S. Cerevisiae. Proc. Natl. Acad. Sci. USA. 96:14360-14365.
  24. Gallina, A., L. Simoncini, S. Garbelli, E. Percivalle, G. Pedrali-Noy, K.S. Lee, and R.L. Erikson, B. Plachter, G. Gerna, and G. Milanesi. 1999. Polo-like kinase 1 as a target for human cytomegalovirus pp65 lower matrix protein. J. Virol. 73:1468-1478.
  25. Lee, K.S., T. Z. Grenfell, F. R. Yarm, and R.L. Erikson. 1998. Mutations of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk. Proc. Natl. Acad. Sci. USA. 95: 9301-9306.
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