The Li laboratory is interested in dissection of molecular mechanisms that regulate cellular stress response and cell death signaling. Regulation of cell cycle and cellular response to DNA damage is critical for genome stability, normal tissue homeostasis, tumorigenesis and cancer treatment. Cells utilize cell cycle checkpoint mechanisms to ensure accurate transmission of genetic material. We have recently identified Cdk5 activator binding protein C53 as a novel regulator of cell cycle and DNA damage response. Our study demonstrated that C53 knockdown leads to cell cycle defects and resistance to genotoxin-induced apoptosis. C53 overexpression abolishes the G2/M checkpoint-mediated Cdk1 inactivation, thereby sensitizing cancer cells to various DNA damage agents. We also found that C53 knockdown results in delayed Cdk1 activation and mitotic entry, while C53 overexpression promotes premature Cdk1 activation. We are currently investigating how C53 modulates Cdk1 activation in normal cell cycle progression and DNA damage response. This study will provide insight into a novel regulatory mechanism for DNA damage-induced apoptosis. It will lay a foundation for further exploitation of this novel protein as a potential therapeutic target in cancer treatment.

Cellular response to ER (endoplasmic reticulum) stress is another focus of the laboratory. Accumulation of misfolded proteins in the ER lumen induces a coordinated cellular response known as the ER stress response or unfolded protein response (UPR). ER stress response is involved in the pathogenesis of many human diseases, including neurodegenerative diseases, diabetes and certain liver and heart diseases. We have recently identified a novel protein complex that play an important role in the control of cellular response to ER stress. Further study will shed light on the molecular mechanism of this important protein complex and its potential role in human diseases.

PUBLICATIONS

1. Chelladurai, B.S., Li, H., Nicholson, A.W. (1991) A conserved sequence element in ribonuclease III processing signals is not required for accurate in vitro enzymatic cleavage. Nucleic Acids Res. 19, 1759-1766.

2. Li, H., Chelladurai, B. S., Zhang, K., Nicholson, A. W. (1993) Ribonuclease III cleavage of a bacteriophage T7 processing signal. Divalent cation specificity, and specific anion effects. Nucleic Acids Res. 21, 1919-1925.

3. Chelladurai, B.S., Li, H., Zhang, K., Nicholson, A.W. (1993) Mutational analysis of a ribonuclease III processing signal. Biochemistry 32, 7549-7558.

4. Li, H. and Nicholson, A. W. (1996) Defining the enzyme binding domain of a ribonuclease III processing signal. Ethylation interference and hydroxyl radical footprinting using catalytically inactive RNase III mutants. EMBO J. 15, 1421-1433.

5. Shi, L., Chen, G., MacDonald, G., Bergeron, L., Li, H., Miura, M., Rotello, R. J., Miller, D. K., Li, P., Seshadri, T., Yuan, J., Greenberg, A. H. (1996) Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B. Proc. Natl. Acad. Sci. USA 93, 11002-11007.

6. Cryns, V. L., Bergeron, L., Zhu, H., Li, H., Yuan, J. (1996) Specific cleavage of alpha-fodrin during Fas- and tumor necrosis factor-induced apoptosis is mediated by an interleukin-1beta-converting enzyme/Ced-3 protease distinct from the poly(ADP-ribose) polymerase protease. J. Biol. Chem. 271, 31277-31282.

7. Li, H., Bergeron, L., Cryns, V., Pasternack, M. S., Zhu, H., Shi, L., Greenberg, A., Yuan, J. (1997) Activation of caspase-2 in apoptosis. J. Biol. Chem. 272, 21010-21017.

8. Haviv, R., Lindenboim, L., Li, H., Yuan, J., Stein, R. (1997) Need for caspases in apoptosis of trophic factor-deprived PC12 cells. J. Neurosci. Res. 50, 69-80.

9. Zhou, B-B., Li, H., Yuan, J., Kirschner, M. W. (1998) Caspase-dependent activation of cyclin-dependent kinases during Fas-induced apoptosis in Jurkat cells. Proc. Natl. Acad. Sci. USA 95, 6786-6790.

10. Li, H., Zhu, H., Xu, C., Yuan, J. (1998) Cleavage of BID by caspase-8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501.

11. Chou, J. J., Li, H., Salvesen, G., Yuan, J. and Wagner, G. (199) Solution structure of Bid, an intracellular amplifier of apoptotic signaling. Cell 96, 615-624.

12. Ruffolo, S. C., Breckenridge, D. G., Nguyen, M., Goping, I. S., Gross, A., Korsmeyer, S. J., Li, H., Yuan, J., Shore, G. C. (2000) BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ 7, 1101-1108.

13. Tong, X. and Li, H. (2004) eNOS protects from prostate cancer cells from TRAIL-induced apoptosis. Cancer Letters 210, 63-71.

14. Fu, T., Blei, A.T., Takamura, N., Lin, T., Guo, D., Li, H., O'Gorman, M.R., Soriano, H.E. (2004) Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. Cell Transplant 13, 667-676.

15. Wu, J., Luo, S., Hai, J., Li, H. (2005) Mammalian CHORD-containing protein 1 is a novel heat shock protein 90-interacting protein. FEBS letters 579, 421-426.

16. Jiang, H., Luo, S., Li, H. (2005) Cdk5 activator binding protein C53 regulates apoptosis induced by genotoxic stress via modulating cyclin B1 phosphorylation J. Biol. Chem. 280, 20651-20659

17. Yang, W., Monroe, J. Zhang, Y., George, D., Bremer, E, Li, H. (2006) Proteasome inhibition induces both pro-and anti-cell death pathways in prostate cancer cells. Cancer Letters 243, 217-227.

18. Zhao, Y., Fedczyna, T. O., McVicker, V., Caliendo, J., Li, H., Pachman, L. M. (2007) Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease. Clin Immunol 125, 165-172.

19. Jiang, H., Wu, J., He, C., Yang, W., Li, H. (2009) A tumor suppressor C53 protein antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation. Cell Research 19, 458-468.

Contact Information:

Children's Memorial Research Center

Northwestern University Feinberg School of Medicine

2300 Children's Plaza, no. 209

Chicago, IL 60614



Tel: (773) 755-6359 (Office)

(773) 755-6542 (Lab)

Fax: (773) 755-6344