The National Institute of Diabetes & Digestive & Kidney Diseases

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.

Cho, J., Shen, H., Yu, H., Li, H., Cheng, T., Lee, S.B. and Lee, B.C. Ewing's sarcoma gene EWS regulates hematopoietic stem cell senescence. (In press, Blood 2010).

Park, J., Kang, S.I., Lee, S.Y., Zhang, X.F., Kim, M.S., Beers, L.F., Lim, D.S. Avruch, J., Kim, H.S. and Lee, S. B.  Tumor Suppressor Ras-Association Domain Family 5 (RASSF5/NORE1) Mediates TNF-a Induced Apoptosis. J. Biol. Chem. 2010; Epub. [Full Text/Abstract]

Hur, W., Rhim, H., Jung, C.K., Kim, J.D., Bae, S.H., Jang, J.W., Yang, J.M., Oh, S.T., Kim, D.G., Wang, H.J., Lee, S.B., and Yoon, S.K.  SOX4 Overexpression Regulates the p53-mediated Apoptosis in Hepatocellular Carcinoma: Clinical Implication and Functional Analysis in vitro. Carcinogenesis 2010; 31:1298-1307. [Full Text/Abstract]

Kim, M.S., Yoon, S.K., Bollig, F., Kitagaki, J., Hur, W.H., Whye, N., Wu, Y.P., Rivera, M.G., Park, J.Y., Kim, H.S., Malik, K., Bell, D., Englert, C., Perantoni, A.O., and Lee, S.B.  A Novel Wilms Tumor 1 (WT1) Target Gene Negatively Regulates the WNT Signaling Pathway. J. Biol. Chem. 2010; 285:14585-14593. [Full Text/Abstract]

Sohn, E.J., Li, H., Reidy, K., Beers, L.F., Christensen, B.L. and Lee, S. B. EWS/FLI1 Oncogene Activates Caspase 3 Transcription and Triggers Apoptosis In Vivo. Cancer Research 2010; 70:1154-1163. [Full Text/Abstract]

Dallosso, A.R., Hancock, A.L., Szemes, M., Moorwood, K., Chilukamarri, L., Tsai, H., Sarkar, A., Barasch, J., Vuononvirta, R., Jones, C., Pritchard-Jones, K, Royer-Pokora, B., Lee, S.B., Owen, C., Malik, S., Feng, Y., Frank, M., Ward, A., Brown, K.W. and Malik, K. Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor. PLoS Genetics 2009; 5(11): e1000745. [Full Text/Abstract]

Choi, J., Oh, S., Lee, D., Oh, H.J., Park, J.Y., Lee, S.B. and Lim, D.S. Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice. PLoS ONE 2009; 4(11): e8011. [Full Text/Abstract]

Li, H., Smolen, G.A., Beers, L.F., Xia, L., Gerald, W., Wang, J., Haber, D.A., and Lee, S.B. Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in Desmoplastic Small Round Cell Tumor. PLoS ONE 2008; 3(6):e2353. [Full Text/Abstract]

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. Clinical Investigation (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 Research (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 Research (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]

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 Research (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]

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. Nature Genetics (17): 309-13, 1997. [Full Text/Abstract]