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Lee, Wen-Hwa

WenHuaLi_120Distinguished Research Fellow


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Telephone: +886-2-27871276
 

 

 

EDUCATION AND POSITIONS HELD:

  • B.S., Biology, National Taiwan Normal University, 1968-1972
  • MS, Biochemistry, National Taiwan University, 1975-1977
  • Ph.D., Molecular Biology, University of California at Berkeley, 1978-1981
  • Postdoctoral, Molecular Biology, University of California at Berkeley, 1981-1982
  • Research Scientist, Cetus Corporation at Berkeley, California, 1982-1983
  • Visiting Scientist, Lawrence Berkeley Laboratory, Berkeley, 1983-1984
  • Assistant Professor, Assoc. Professor, 1984-1990, Professor, 1990-1991, University of California at San Diego
  • Professor/Chairman, Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 1991-2003
  • Member, NIH Cell Biology & Physiology Study Section II, 1992-1996
  • Member, NCI Cancer Center Study Group IRG A, 1998-2002
  • Donald Bren Professor, 2003-2013, Chairman, 2005-2008, Department of Biological Chemistry, University of CA at Irvine
  • Distinguished Research Fellow, Genomics Research Center, Academia Sinica, 2012-present
  • President, China Medical University(on secondment), 2014-present

HONORS:

  • A.P. McDermott Distinguished University Professor, UTHSC-SA, 1991
  • NIH Director Lectureship, 1991
  • Outstanding Scientific Achievement, SCBA, 1992
  • Alcon Research Award, 1994
  • Member, Sinica Academia, ROC, 1994
  • F.E. Shideman-Sterling Award, Univ. of Minnesota, 1999
  • Presidential Award, SCBA, 2001
  • Outstanding Alumni Award, National Taiwan Normal University, 2002
  • First Class Medal, Dept. of Health, Taiwan, 2002
  • Inducted Member, Texas Hall of Fame for Science, Mathematics and Technology, 2003
  • Donald Bren Chair Professorship, Univ. California , Irvine, 2003

RESEARCH INTERESTS:

This lab co-discovered the first human tumor suppressor gene, Retinoblastoma gene (RB), in late 1980 that plays essential roles in maintaining genomic stability and preventing tumor formation. Re-introduction of the wild-type Rb or p53 mediated by viral vectors suppresses tumor formation in animal studies. In addition, we have elucidated RB interaction networks, which modulate RB suppressing activity. One of the RB-interacting proteins, Hec1, is overly expressed in most cancer cells and plays essential roles in chromosome segregation by interacting 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. We have identified small molecules that disrupt the interaction between Nek2 and Hec1, and may offer a novel agent to treat cancer.

In addition, we worked on two human breast cancer susceptibility genes, BRCA1 & BRCA2 and 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, which 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 to activate the G2/M checkpoint. Small molecules that disrupt the interaction between BRC repeat and Rad51 have been isolated. These small compounds offer a potential to develop new combinatorial treatment with chemotherapy or radiation therapy.

SELECTED PUBLICATIONS

  • Chang MC, Chang YT, Chen JY, Jeng YM, Yang CY, Tien YW, Yang SH, Chen HL, Liang TY, Wang CF, Lee EY, Chang YC, Lee WH, 2016, “Clinical Significance of Circulating Tumor Microemboli as a Prognostic Marker in Patients with Pancreatic Ductal Adenocarcinoma.”, Clinical chemistry, 62(3), 505-513. (SCI)
  • Hu CM, Zhu J, Guo XE, Chen W, Qiu XL, Ngo B, Chien R, Wang YV, Tsai CY, Wu G, Kim Y, Lopez R, Chamberlin AR, Lee EY, Lee WH, 2015, “Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism.”, Oncogene, 34(10), 1220-1230. (SCI)
  • Chen PJ, Weng JY, Hsu PH, Shew JY, Huang YS, Lee WH, 2015, “NPGPx modulates CPEB2-controlled HIF-1alpha RNA translation in response to oxidative stress.”, Nucleic acids research, 43(19), 9393-9404. (SCI)
  • Wu HH, Hwang-Verslues WW, Lee WH, Huang CK, Wei PC, Chen CL, Shew JY, Lee EY, Jeng YM, Tien YW, Ma C, Lee WH, 2015, “Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines.”, Journal of experimental medicine, 212(3), 333-349. (SCI)
  • Lee WH, Wu HH, Huang CK, 2015, “Targeting interleukin-17 receptors.”, Oncotarget, 6(21), 18244-18245. (SCI)
  • Ngo B, Hu CM, Guo XE, Ngo B, Wei R, Zhu J, Lee WH, 2013, “Complementary Interhelical Interactions between Three Buried Glu-Lys Pairs within Three Heptad Repeats Are Essential for Hec1-Nuf2 Heterodimerization and Mitotic Progression.”, The Journal of biological chemistry, 288(48), 34403-34413. (SCI)
  • He S, Ni D, Ma B, Lee JH, Zhang T, Ghozalli I, Pirooz SD, Zhao Z, Bharatham N, Li B, Oh S, Lee WH, Takahashi Y, Wang HG, Minassian A, Feng P, Deretic V, Pepperkok R, Tagaya M, Yoon HS, Liang C, 2013, “PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex.”, Nature cell biology, 15(10), 1206-1219. (SCI)
  • Yi-Cheng Chang, Yu-Hsiang Yu, Jin-Yuh Shew ,Wei-Jei Lee, Juey-Jen Hwang, Yen-Hui Chen, Yet-Ran Chen, Pei-Chi Wei, Lee-Ming Chuang, Wen-Hwa Lee*., 2013, “Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human.”, EMBO Molecular Medicine, 5(8), 1165-1179. (SCI)
  • Lin LF, Li CF, Wang WJ, Yang WM, Wang DD, Chang WC, Lee WH, Wang JM. , 2013, “Loss of ZBRK1 Contributes to the Increase of KAP1 and Promotes KAP1-Mediated Metastasis and Invasion in Cervical Cancer ”, PLoS One, 8(8), e73033. (SCI)
  • Wendy W. Hwang-Verslues, Po-Hao Chang, Yung-Ming Jeng, Wen-Hung Kuo, Pei-Hsun Chiang, Yi-Cheng Chang, Tsung-Han Hsieh, Fang-Yi Su, Liu-Chen Lin, Serena Abbondante, Cheng-Yuan Yang, Huan-Ming Hsu, Jyh-Cherng Yu, King-Jen Chang, Jin-Yuh Shew, Eva Y.-H. P. Lee, Wen-Hwa Lee*., 2013, “Loss of corepressor PER2 under hypoxia upregulates OCT1-mediated EMT gene expression and enhances tumor malignancy.”, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(30), 12331-12336. (SCI)
  • Zhu J, Zhou L, Wu G, Konig H, Lin X, Li G, Qiu XL, Chen CF, Hu CM, Goldblatt E, Bhatia R, Chamberlin AR, Chen PL, Lee WH, 2013, “A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia.”, EMBO molecular medicine, 5(3), 353-365. (SCI)
  • Wei PC, Wang ZF, Lo WT, Su MI, Shew JY, Chang TC, Lee WH*., 2013, “A cis-element with mixed G-quadruplex structure of NPGPx promoter is essential for nucleolin-mediated transactivation on non-targeting siRNA stress.”, Nucleic acids research, 41(3), 1533-1543. (SCI)
  • Chang PH, Hwang-Verslues WW, Chang YC, Chen CC, Hsiao M, Jeng YM, Chang KJ, Lee EY, Shew JY*, Lee WH*, 2012, “Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway.”, Cancer research, 72(18), 4652-4661. (SCI)
  • Tyan SW, Hsu CH, Peng KL, Chen CC, Kuo WH, Lee EY, Shew JY, Chang KJ, Juan LJ*, Lee WH*, 2012, “Breast cancer cells induce stromal fibroblasts to secrete ADAMTS1 for cancer invasion through an epigenetic change.”, PLoS One, 7(4), e35128. (SCI)
  • Wei PC, Hsieh YH, Su MI, Jiang X, Hsu PH, Lo WT, Weng JY, Jeng YM, Wang JM, Chen PL, Chang YC, Lee KF, Tsai MD, Shew JY*, Lee WH*, 2012, “Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease.”, Molecular cell, 48(5), 747-759. (SCI)
  • Chen PL, Chen CF, Chen Y, Guo XE, Huang CK, Shew JY, Reddick RL, Wallace DC, Lee WH, 2012, “Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan.”, Oncogene, 32(9), 1193-1201. (SCI)
  • Wei PC, Lo WT, Su MI, Shew JY, Lee WH*., 2012, “Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress.”, Nucleic acids research, 40(1), 323-332. (SCI)
  • Furuta S, Jeng YM, Zhou L, Huang L, Kuhn I, Bissell MJ, Lee WH, 2011, “IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells.”, Science translational medicine, 3(78), 78ra31. (SCI)
  • Hwang-Verslues WW, Chang PH, Wei PC, Yang CY, Huang CK, Kuo WH, Shew JY, Chang KJ, Lee EY, Lee WH, 2011, “miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.”, Oncogene, 30(21), 2463-2474. (SCI)
  • Lin LF, Chuang CH, Li CF, Liao CC, Cheng CP, Cheng TL, Shen MR, Tseng JT, Chang WC, Lee WH, Wang JM, 2010, “ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer.”, Cancer research, 70(1), 192-201. (SCI)
  • Wu G, Qiu XL, Zhou L, Zhu J, Chamberlin R, Lau J, Chen PL, Lee WH, 2008, “Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal.”, Cancer research, 68(20), 8393-9. (SCI)
  • Furuta S, Wang JM, Zeng WS, Jeng YM, Jiang Xzi, Gu BN, Chen PL, Lee EY, Lee WH , 2006, “Inactivation of BRCA1/CtIP tumor suppressors releases ANG1 repression mediated by ZBRK1 and leads to pronounced vasculature and growth of breast tumor.”, Cancer Cell, 10: 13-24.
  • Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY, 2006, “Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist.”, Science, 314(5804), 1467-70. (SCI)
  • Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP, 2002, “BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.”, SCIENCE, 297(5588), 1837-48. (SCI)
  • Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y, Lee EY, Lee WH, 2000, “Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response.”, Nature, 406(6792), 210-5. (SCI)
  • Zheng L, Pan H, Li S, Flesken-Nikitin A, Chen PL, Boyer TG, Lee WH, 2000, “Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1.”, Molecular cell, 6(4), 757-68. (SCI)
  • Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH, 1999, “Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.”, SCIENCE, 285(5428), 747-50. (SCI)
  • Utomo AR, Nikitin AY, Lee WH, 1999, “Temporal, spatial, and cell type-specific control of Cre-mediated DNA recombination in transgenic mice.”, Nature biotechnology, 17(11), 1091-6. (SCI)
  • Riley DJ, Nikitin AY, Lee WH, 1996, “Adenovirus-mediated retinoblastoma gene therapy suppresses spontaneous pituitary melanotroph tumors in Rb+/- mice.”, Nature medicine, 2(12), 1316-21. (SCI)
  • Chen Y, Chen CF, Riley DJ, Allred DC, Chen PL, Von Hoff D, Osborne CK, Lee WH, 1995, “Aberrant subcellular localization of BRCA1 in breast cancer.”, Science, 270(5237), 789-91. (SCI)
  • Goodrich DW, Lee WH, 1992, “Abrogation by c-myc of G1 phase arrest induced by RB protein but not by p53.”, Nature, 360(6400), 177-9. (SCI)
  • Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A, 1992, “Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.”, Nature, 359(6393), 288-94. (SCI)
  • Huang S, Lee WH, Lee EY, 1991, “A cellular protein that competes with SV40 T antigen for binding to the retinoblastoma gene product.”, Nature, 350(6314), 160-2. (SCI)
  • Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH, 1991, “The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle.”, Cell, 67(2), 293-302. (SCI)
  • Chen PL, Chen YM, Bookstein R, Lee WH, 1990, “Genetic mechanisms of tumor suppression by the human p53 gene.”, Science, 250(4987), 1576-80. (SCI)
  • Bookstein R, Shew JY, Chen PL, Scully P, Lee WH, 1990, “Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene.”, Science, 247(4943), 712-5. (SCI)
  • Chen PL, Scully P, Shew JY, Wang JY, Lee WH, 1989, “Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation.”, Cell, 58(6), 1193-8. (SCI)
  • Ludlow JW, DeCaprio JA, Huang CM, Lee WH, Paucha E, Livingston DM, 1989, “SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family.”, Cell, 56(1), 57-65. (SCI)
  • Lee EY, To H, Shew JY, Bookstein R, Scully P, Lee WH, 1988, “Inactivation of the retinoblastoma susceptibility gene in human breast cancers.”, Science, 241(4862), 218-21. (SCI)
  • Huang HJ, Yee JK, Shew JY, Chen PL, Bookstein R, Friedmann T, Lee EY, Lee WH, 1988, “Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells.”, Science, 242(4885), 1563-6. (SCI)
  • DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsilio E, Paucha E, Livingston DM, 1988, “SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene.”, Cell, 54(2), 275-83. (SCI)
  • Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY, 1987, “Human retinoblastoma susceptibility gene: cloning, identification, and sequence.”, Science, 235(4794), 1394-9. (SCI)
  • Lee WH, Shew JY, Hong FD, Sery TW, Donoso LA, Young LJ, Bookstein R, Lee EY, 1987, “The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity.”, Nature, 329(6140), 642-5. (SCI)
  • Lee WH, Murphree AL, Benedict WF, 1984, “Expression and amplification of the N-myc gene in primary retinoblastoma.”, Nature, 309(5967), 458-60. (SCI)