Sean Bong Lee, Ph.D. : NIDDK

Sean Bong Lee, Ph.D.

NIDDK, National Institutes of Health
Building 10, Room 9D11
10 Center Dr.
Bethesda, MD 20892-1821
Tel: 301-496-9739
Fax: 301-480-0638

Education / Previous Training and Experience:
B.S., SUNY at Buffalo, 1989
Ph.D., SUNY Health Science Center at Brooklyn, 1994

Research Statement:

The primary interest of this laboratory is to understand how perturbations during normal development process can lead to cancer. In particular, Wilms' tumor, a childhood kidney cancer, serves as a paradigm for studying development and cancer in our laboratory.

The Wilms' tumor suppressor gene, WT1, is mutated in 10-15% of Wilms' tumor and it encodes a transcription factor with four C2H2 zinc fingers as its DNA binding domain. In addition to Wilms' tumor, mutations inWT1 are found in other human diseases such as WAGR, Danys-Drash and Frasier syndromes, all of which display developmental defects in both kidneys and gonads. WAGR and Danys-Drash patients also suffer from an increased risk of Wilms' tumor. WT1 is proposed to regulate the transcription of genes that are critical for the initiation and differentiation of kidneys, gonads, spleen, and the adrenal gland since wt1-null mouse embryos lack all of these organs. Our laboratory is focused on the identification of WT1 target genes that initiate and coordinate organogenesis of the kidney and other affected tissues, as well as identifying WT1-containing complexes. We are using microarray and chromatin-IP techniques to identify and verify potential WT1-target genes. Identification of the target genes and defining their role during development will provide further insights to the development of Wilms' tumor and organogenesis in general.

Ewing's sarcoma and related small round cell tumors have a distinct characteristic which involves chromosomal translocation of the Ewing's sarcoma gene (EWS) to various transcription factor-encoding genes. The prototype is the EWS/Fli-I translocation found in about 80% of Ewing's sarcoma. Desmoplastic small round cell tumor (DSRCT) is another example of chromosomal translocation that leads to the fusion of EWS gene to the WT1 gene. Current treatment for DSRCT is minimally effective and the pathways that are responsible for generating the tumor are largely undefined. To identify the mechanisms of tumorigenesis in DSRCT, we are attempting to generate a mouse model of DSRCT by expressing the EWS/WT1 gene product in mouse embryonic stem cells. The mouse model, if successful, will then be used to dissect molecular pathways that are responsible for the formation of DSRCT, which can lead to the development of new therapeutics against DSRCT-specific molecular targets.

Selected Publications:

Li H, Watford W, Li C, Parmelee A, Bryant MA, Deng C, O''shea J, Lee SB Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development. J Clin Invest(117): 1314-1323, 2007. [Full Text/Abstract]

Kim HS, Kim MS, Hancock AL, Harper JC, Park JY, Poy G, Perantoni AO, Cam M, Malik K, Lee SB Identification of novel WT1 target genes implicated in kidney development. J Biol Chem, 2007. [Full Text/Abstract]

Kim HS, Li H, Cevher M, Parmelee A, Fonseca D, Kleiman FE, Lee SB DNA damage-induced BARD1 phosphorylation is critical for the inhibition of messenger RNA processing by BRCA1/BARD1 complex. Cancer Res (66): 4561-5, 2006. [Full Text/Abstract]

Toretsky JA, Erkizan V, Levenson A, Abaan OD, Parvin JD, Cripe TP, Rice AM, Lee SB, Uren A Oncoprotein EWS-FLI1 Activity Is Enhanced by RNA Helicase A. Cancer Res (66): 5574-81, 2006. [Full Text/Abstract]

Srichai MB Konieczkowski M Padiyar A Konieczkowski DJ Mukherjee A Hayden PS Kamat S El-Meanawy MA Khan S Mundel P Lee SB Bruggeman LA Schelling JR Sedor JR A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus. J Biol Chem (279): 14398-408, 2004. [Full Text/Abstract]

Lee, S.B., Li, H., and Kim, H.S. The role of WT1 in Development and Disease. In: Zinc Finger Proteins. Iuchi, S. and Kuldell, N., editors. Landes Bioscience, 2004.

Palmer RE Lee SB Wong JC Reynolds PA Zhang H Truong V Oliner JD Gerald WL Haber DA Induction of BAIAP3 by the EWS-WT1 chimeric fusion implicates regulated exocytosis in tumorigenesis. Cancer Cell (2): 497-505, 2002. [Full Text/Abstract]

Wong JC Lee SB Bell MD Reynolds PA Fiore E Stamenkovic I Truong V Oliner JD Gerald WL Haber DA Induction of the interleukin-2/15 receptor beta-chain by the EWS-WT1 translocation product. Oncogene (21): 2009-19, 2002. [Full Text/Abstract]

Wang W Lee SB Palmer R Ellisen LW Haber DA A functional interaction with CBP contributes to transcriptional activation by the Wilms tumor suppressor WT1. J Biol Chem (276): 16810-6, 2001. [Full Text/Abstract]

Lee SB Kim SH Bell DW Wahrer DC Schiripo TA Jorczak MM Sgroi DC Garber JE Li FP Nichols KE Varley JM Godwin AK Shannon KM Harlow E Haber DA Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res (61): 8062-7, 2001. [Full Text/Abstract]

Lee SB Haber DA Wilms tumor and the WT1 gene. Exp Cell Res (264): 74-99, 2001. [Full Text/Abstract]

Lee SB Huang K Palmer R Truong VB Herzlinger D Kolquist KA Wong J Paulding C Yoon SK Gerald W Oliner JD Haber DA The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell (98): 663-73, 1999. [Full Text/Abstract]

Maheswaran S Englert C Zheng G Lee SB Wong J Harkin DP Bean J Ezzell R Garvin AJ McCluskey RT DeCaprio JA Haber DA Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. Genes Dev (12): 1108-20, 1998. [Full Text/Abstract]

Lee SB Kolquist KA Nichols K Englert C Maheswaran S Ladanyi M Gerald WL Haber DA The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour. Nat Genet (17): 309-13, 1997. [Full Text/Abstract]

Page last updated: December 15, 2008

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