molecular cancer genetics, tumor suppressor gene functions, cancer progression, and novel therapy, Hec1,
Donal Bren Professor, UCI (2003-). Inducted Member, Texas Hall of Fame for Science, Mathematics and Technology (2003); First Class Medal, Dept. of Health, Taiwan (2002); Outstanding Alumni Award, National Taiwan Normal University (2002); Presidential Award, SCBA (2001); F.E. Shideman-Sterling Award, Univ. of Minnesota (1999); Member, Sinica Academia, ROC (1994); Alcon Research Award (1994); Outstanding Scientific Achievement (SCBA) (1992); NIH Director Lectureship (1991); A.P. McDermott Distinguished University Professor, UTHSC-SA (1991).
1982 – 1983 - Research Scientist, Cetus Corporation, Berkeley, California
1983 – 1984 - Visiting Scientist, Lawrence Berkeley Laboratory, Berkeley
1984 - 1991 - Assist. Professor, Assoc. Professor, & Professor, University of California, San Diego
1991 – Aug., 2003 - Professor/Chairman, Department of Molecular Medicine/Institute of Biotechnology
Effect. Sept., 2003 - Donald Bren Professor, Department of Biological Chemistry, University of CA, Irvine
1992 – 1996 - Member, NIH Cell Biology & Physiology Study Section II
1998 – 2002 - Member, NCI Cancer Center Study Group IRG A
Tumor suppressor genes play essential roles in maintaining genomic stability and preventing tumor formation. This group of genes has diverse cellular activity ranging from serving as cell cycle regulators, DNA damage signal transducers and modulators for chromosome segregation. Because genetic instability is the most important hallmark of cancer, tumor suppressors with the function directly involved in the process of chromosome segregation and DNA repair provide potential links between carcinogenesis and genomic instability. Both p53 and Rb, two key tumor suppressors, are inactivated frequently in human cancers. Re-introduction of the wild-type Rb or p53 mediated by viral vectors suppresses tumor formation in animal study, indicating their tumor suppressing ability. In addition, ample opportunity exists for targeting their interaction networks to modulate their suppressing activity. Small-molecules that bind MDM2 in the p53-binding pocket recently identified to activate the p53 pathway in cancer cells, leading to cell cycle arrest and growth inhibition of human tumor xenografts in nude mice. This finding offers a new strategy for targeting tumor suppressor networks. In an attempt to elucidate Rb network, we have identified Hec1, which is overly expressed in most cancer cells and plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the G2/M phase. Inactivation of Hec1 led to cell death due to abnormal chromosomal segregation. Importantly, Hec1 is phosphorylated by a mitotic kinase, Nek2, which is essential for Hec1 function in chromosome segregation. Thus, identifying small molecules that disrupt the interaction between Nek2 and Hec1 and thereby inactivate Hec1 may offer a novel strategy to treat cancer.
On the other hand, mutation of tumor suppressor BRCA genes is rarely occurred in sporadic human cancer. Human cancer cells and mouse cells deficient in BRCA1 or BRCA2 exhibit radiation hypersensitivity, revealing a potential role in the cellular response to DNA damage. Functional analyses of the BRCA1 and BRCA2 gene products have established their dual participation in transcription regulation and DNA damage repair. BRCA1 has been shown to associate directly with the RAD50/MRE11/NBS1 complex that functions in both non-homologous end-joining and homologous recombination repair of DNA double-strand breaks. The BRCA2 via its BRC repeats binds to RAD51, which catalyzes homologous DNA pairing and DNA strand exchange in an in vitro recombination reaction. Expression of a wild-type BRC repeat disrupted this interaction and rendered cells hypersensitive to gamma-irradiation and failed in G2/M checkpoint. These results suggest that the interaction between BRCA2 and Rad51 or BRCA1 and Rad50 complex offers a potential target to develop new combinatory treatment with traditional chemotherapy or radiation therapy.
(Partial listing from total of 183):
Durfee T, Becherer K, Chen P-L, Yeh S-H, Yang Y, Kilburn A, Lee W-H and Elledge S: The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes & Dev., 7: 555-569, (1993).
Bignon Y-J, Chen Y, Chang C-Y, Riley D, Windle J, Mellon P, and Lee W-H: Expression of a retinoblastoma transgene results in dwarf mice. Genes & Dev., 7: 1654-1662 (1993).
Shan B and Lee W-H: Deregulated Expression of E2F-1 Induces S-Phase Entry and Leads to Apoptosis. Mol. & Cell. Biol., 14: 8166-8173 (1994).
Shan B, Durfee T, and Lee W-H: Disruption of Rb/E2F-1 interaction by single point mutations in E2F-1 enhances S-phase entry and apoptosis. Proc. Natl. Acad. Sci., 93: 679-684 (1996).
Liu C-Y, Flesken-Nikitin A, Li S, Zeng Y, and Lee W-H: Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early development. Genes & Dev., 10: 1835-1843 (1996).
Chen P-L, Riley DJ, Chen Y, and Lee W-H: Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes & Dev., 10: 2794-2804 (1996).
Riley DJ, Nikitin AY, and Lee W-H: Adenovirus-mediated Retinoblastoma gene therapy suppresses spontaneous pituitary melanotroph tumors in RB +/- mice. Nature Medicine, 2: 1316-1321 (1996).
Chen Y, Riley DJ, Chen P-L, and Lee W-H: HEC, a Novel Nuclear Protein Rich in Leucine Heptad Repeats Specifically Involved in Mitosis. Mol. & Cell. Biol., 17: 6049-6056 (1997).
Riley DJ, Liu C-Y, and Lee W-H: Mutations of N-terminal Regions Render the Retinoblastoma Protein Insufficient for Functions in Development and Tumor Suppression. Mol. & Cell. Biol. 17: 7342-7352 (1997).
Chen P-L, Chen C-F, Chen Y, Xiao J, Sharp ZD, and Lee W-H: The BRC Repeats In BRCA2 Are Critical for RAD51 Binding & Resist. to Methyl Methanesulfonate Treatment. Proc. Natl. Acad. Sci.,95: 5287-5292 (1998).
Nikitin A Yu, Juarez-Perez MI, Li S, Huang L, and Lee W-H: RB-mediated suppression of multiple neuroendocrine neoplasia and lung metastases in RB +/- mice. Proc. Natl. Acad. Sci., 96: 3916-3921 (1999).
Chen Y, Chen P-L, Chen C-F, Sharp ZD, and Lee W-H: Thyroid hormone, T3-dependent phosphorylation and translocation of Trip230 from the Golgi complex to the nucleus. Proc. Natl. Acad. Sci., 96: 4443-4448 (1999).
Li S, Chen P-L, Subramanian T, Chinnadurai G, Tomlinson G, Osborne CK, Sharp ZD, and Lee W-H: Binding of CtIP to the BRCT Repeats of BRCA1 Involved in the Transcription Regulation of p21 Is Disrupted Upon DNA Damage. J. Biol. Chem., 274: 11334-11338 (1999).
Zhong Q, Chen C-F, Li S, Chen Y, Wang C-C, Xiao J, Chen P-L, Sharp ZD, Lee W-H: Association of BRCA1 with the hRad50-hMre11-p95 Complex and the DNA Damage Response. Science, 285:747-750 (1999).
Utomo A, Nikitin AY, and Lee W-H: Temporal, Spatial, and Cell Type-Specific Control of CRE-Mediated DNA Recombination in Transgenic Mice. Nature Biotechnology, 17: 1091-1096 (1999).
Chen C-F, Chen P-L, Zhong Q, Sharp ZD, and Lee W-H: Expression of BRC Repeats in Breast Cancer Cells Disrupts the BRCA2-Rad51 Complex and Leads to Radiation Hypersensitivity and Loss of G2/M Checkpoint Control. J. Biol. Chem., 274: 32931-32935 (1999).
Zheng L, Chen Y, Riley DJ, Chen P-L, and Lee W-H: Retinoblastoma Protein Enhances the Fidelity of Chromosome Segregation Mediated by hsHec1p. Mol. & Cell. Biol., 20: 3529-3537 (2000).
Li S, Ting N S.Y., Zheng L, Chen P-L, Ziv Y, Shiloh Y, Lee E Y-H, and Lee W-H: Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature. 406:210-215 (2000).
Zheng L, Pan H, Li S, Flesken-Nikitin A, Chen P-L, Boyer T, and Lee W-H: Sequence-Specific Transcriptional Corepressor Function for BRCA1 through a Novel Zinc Finger Protein, ZBRK1. Molec. Cell, 6: 757-768 (2000).
Xiao J, Liu C-C, Chen P-L, and Lee W-H: RINT-1, a Novel Rad50-interacting Protein, Participates in Radiation-induced G2/M Checkpoint Control. J. Biol. Chem. 276: 6105-6111 (2001).
Nikitin AY, Shan B, Flesken-Nikitin A, Chang K-H, and Lee W-H: The Retinoblastoma Gene Regulates Somatic Growth during Mouse Development. Cancer Research, 61: 3110-3118 (2001).
Zheng L, Annab LA, Afshari CA, Lee W-H, and Boyer TG: BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad. Sci. USA, 98: 9587-9592 (2001).
Zheng L, Flesken-Nikitin A, Chen P-L, and Lee W-H: Deficiency of Retinoblastoma Gene in Mouse Embryonic Stem Cells Leads to Genetic Instability. Cancer Research, 62: 2498-2502 (2002).
Zhong Q, Boyer TG, Chen P-L, and Lee W-H: Deficiency in nonhomologous end joining activity in cell free extracts from BRCA1 null fibroblasts. Cancer Research 62: 3966-3970 (2002).
Zhong Q, Chen C-F, Chen P-L, and Lee W-H: BRCA1 facilitates micro-homologous mediated end-joining of DNA double-strand breaks. J. Biol. Chem., 277: 28641-28647 (2002).
Nikitin A, Liu C-Y, Flesken-Nikitin A, Chen C-F, Chen P-L, and Lee W-H: Cell Lineage-specific Effects Associated with Multiple Deficiencies of Tumor Susceptibility Genes in Msh2-/- Rb+/- Mice. Cancer Research, 62: 5134-5138 (2002).
Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen P-L, Lee W-H, and Pavletich NP: BRCA2 Function in DNA Binding and Recombination from a BRCA2-DSS1-ssDNA Structure. Science, 297: 1837-1848 (2002). (Research article with commentary and cover.)
Chen Y, Riley DJ, Zheng L, Chen P-L, and Lee W-H: Phosphorylation of the Mitotic Regulator Protein Hec1 by Nek2 Kinase Is Essential for Faithful Chromosome Segregation. J. Biol. Chem., 277: 49408-49416 (2002).
Wu G-K, Jiang X-Z, Lee W-H, and Chen P-L: Assembly of functional ALT associated PML bodies requires NBS1. Cancer Research, 63: 2589-2595 (2003).
Sharp ZD, Lee W-H, Nikitin AY, Flesken-Nikitin A, Ikeno Y, Reddick R, Richardson AG, Nelson JF. Minimal effects of dietary restriction on neuroendocrine carcinogenesis in Rb+/- mice. Carcinogenesis. 2003 24:179-83.
Yun, J and Lee, W-H: Degradation of Transcription repressor ZBRK1 through the ubiquitin-proteasome pathway relieves repression of Gadd45a upon DNA damage. Mol. Cell Biol. 23:20,7305-7314 (2003).
Lin HR, Nicholas SY Ting JQ, Lee, WH. “M-phase specific phosphorylation of BRCA2 by Polo-like Kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex.” J Biol Chem 278:35979-35987, 2003.
Lin, H-R., Ting, N. S.Y., Qin, J., Lee, W-H. M Phase-specific Phosphorylation of BRCA2 by Polo-like Kinase 1 Correlates with the Dissociation of the BRCA2-P/CAF Complex. J. Biol. Chem. 278:38:35979-35987 (2003).
Shu Z, Chen C-F, Chen P-L, Lee W-H: Purified human SUV3p exhibits multiple substrate unwinding activity upon conformational change. Biochem. 43: 4781-4790 (2004).
Utomo A., Jiang X., Furuta S., Yun J., Levin D.S., Wanf Y-C. J., Desai K V., Green J E., Chen P-L., and Lee W-H. : Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells. J. Biol Chem. In press. (2004).
“BRCA1 and transcriptional control in DNA damage response”
This grant was initiated in 2002 and will support until 2006
NCI / NIH R01
“Cancer Suppression by the Retinoblastoma Gene”
This grant was initiated in 1990 and will support until 2003
NCI / NIH (Part II)
“Mouse Cancer Models by Regulated Inactivation
of Tumor Suppressor Genes”
Grant Duration: Oct., 1999 – Sept., 2004
NCI / NIH
Program Project Director, Project 4 and Animal core Leader
“DNA Repair and Tumor Suppressor Genes”
Grant Duration: Mar. 2000 – Feb. 2004
USAMRDC (Center Grant)
Breast Cancer Center in Excellence
Part II “Small molecules disrupt the interaction between BRCA protein and repair proteins”
This grant was initiated in Aug 2002 and will support until 2006
Training grant Director
“Training Program in the Molecular Basis of Breast Cancer”
This grant was initiated in 1994 and will support until 2003
NCI / NIH
SACI Cancer Center, Program Leader
Grant Duration: Aug., 1998 – July 2002
Alcon Research Award
awarded in 1994
Postdoc. Fellowship for Qing Gao, MD
This grant was initiated in Aug 2002 and will support until 2005
Koman breast cancer foundation
Postdoc fellowship for Nicholas Ting, PhD
This grant was initiated in Aug 2001 and will support until 2004
NEI / NIH R01-
“Hec1 as molecular target for therapeutic application”
This grant is a continuation of 18 years’ RB gene study.