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Sean B. Lee, PhD

Sean B. Lee, PhD


Associate Professor


Office Address:

Tulane University School of Medicine
Department of Pathology
1700 Tulane Ave. Room 808
New Orleans, LA 70112
Phone: 504-988-1331
Fax: 504-988-7389
Email: slee30@tulane.edu

Education:

1989     B.S.     SUNY at Buffalo

1994     Ph.D.   SUNY Health Science Center at Brooklyn

Postgraduate Training

1995 – 2001     Postdoctoral Fellow, Mentor: Daniel A Haber, M.D., Ph.D. Massachusetts General Hospital Cancer Center/Harvard Medical School


Faculty Appointments

2001 – 2012     Principal Investigator, Genetics of Development and Disease Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health

2012 –              Associate Professor, Tulane University School of Medicine

Research Interests

The primary interest of our laboratory is to understand how oncogenic events such as a chromosomal translocation lead to cancer. Ewing's sarcoma and related small round cell tumors have a distinct characteristic, which involves a chromosomal translocation of the Ewing's sarcoma gene (EWS) to various transcription factor-encoding genes. The prototype is the EWS-FLI1 translocation found in about 80% of Ewing's sarcoma. Desmoplastic small round cell tumor (DSRCT) is another chromosomal translocation that leads to the fusion of EWS gene to the WT1 gene. Current treatments for DSRCT and metastatic Ewing sarcoma are minimally effective and the pathways that are responsible for generating these tumors are largely undefined. To identify the oncogenic mechanisms of Ewing sarcoma and DSRCT, we generated genetically-engineered mice expressing the chromosomal translocation gene products, EWS-FLI1 or EWS/WT1, respectively. We will utilize these mice to dissect molecular pathways that drive the development of these two cancers. Identification of the deregulated oncogenic pathways will facilitate the development of new therapeutic approaches against these lethal cancers.

A second major interest in our laboratory is to understand the normal functions of EWS gene. We inactivated EWS in the mouse and showed that EWS has novel roles in B-cell development, meiosis, and senescence. We are continuing to dissect the multifunctional roles that EWS play in various organ development and homeostasis.

Bibliography

Manuscripts in Peer-Reviewed Journals:

1.    Lee, D., Park, S.J., Sung, K.S., Park, J., Lee, S.B., Park, S.Y., Lee, H.J., Ahn, J.W., Choi, S.J., Lee, S.G., Kim, S.H., Kim, D.H., Kim, J.K., Kim, Y.S., and Choi, C.Y.  Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1. EMBO Reports 2012; 13:163-169.

2.    Park, B.H., Lee, S.B., Stolz, D. B., Lee, Y.J. and Lee, B.C. Synergistic interactions between heregulin and peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist in breast cancer cells. J. Biol. Chem. 2011; 286:20087-20099.

3.    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. Blood 2011;117:1156-1166.

4.    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-α Induced Apoptosis. J. Biol. Chem. 2010; 285:35029-35038.

5.    Cevher M.A., Zhang, X., Fernandez, S., Kim, S., Baquero, J., Nilsson, P., Lee, S.B., Virtanen, A., Kleiman, F.E. Nuclear deadenylation/polyadenylation factors regulate 3' processing in response to DNA damage. EMBO J. 2010; 29:1674-87.

6.    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.

7.    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.

8.    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.

9.    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     Genet. 2009; 5(11): e1000745.

10.    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.

11.    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.

12.    Li, H., Watford, W., Li, C., Parmelee, A., Bryant, M.A., Deng, C., O'shea, J., and Lee, S.B. Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development. J Clin. Invest. 2007; 117:1314-1323.

13.    Kim, H.S., Kim, M.S., Hancock, A.L., Harper, J.C., Park, J.Y., Poy, G., Perantoni, A.O., Cam, M., Malik, K., and Lee, S.B. Identification of novel WT1 target genes implicated in kidney development. J Biol. Chem. 2007; 282:16278-16287.

14.    Kim, H.S., Li, H., Cevher, M., Parmelee, A., Fonseca, D., Kleiman, F.E., and Lee, S.B. DNA damage-induced BARD1 phosphorylation is critical for the inhibition of pre-mRNA processing by BRCA1/BARD1 complex. Cancer Research 2006; 66:4561-4565.

15.    Toretsky, J.A., Erkizan, V., Levenson, A., Abaan, O.D., Parvin, J.D., Cripe, T,P., Rice, A.M., Lee, S.B., and Uren, A. Oncoprotein EWS-FLI1 Activity Is Enhanced by RNA Helicase A. Cancer Research 2006; 66:5574-5581.

16.    O’Reilly, S.M., Leonard, M.O., Pouliot, M., Lee, S.B., and Taylor, C.T. Hypoxia induces intestinal epithelial amphiregulin gene expression in a CREB-dependent manner. Am. J Physiol. Cell Physiol. 2006; 290: C592-C600.

17.    Srichai, M.B., Konieczkowski, M., Padiyar, A., Konieczkowski, D.J., Mukherjee, A., Hayden, P.S., Kamat, S., El-Meanawy, M.A., Khan, S., Mundel, P., Lee, S.B., Bruggeman, L.A., Schelling, J.R., and Sedor, J.R. A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus.  J Biol Chem. 2004; 279(14):14398-14408.

18.    Shao, J., Lee, S.B., Guo, H., Evers, B.M., and Sheng, H.  Prostaglandin E2 stimulates the growth of colon cancer cells via induction of amphiregulin.  Cancer Research 2003; 63(17):5218-23.

19.    Lee, B.C., Cheng, T., Adams, G.B., Attar, E.C., Miura, N., Lee, S.B., Saito, Y., Olszak, I., Dombkowski, D., Olson, D.P., Hancock, J., Choi, P.S., Haber, D.A., Luster, A., and Scadden, D.T.  P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells. Genes & Development 2003; 17:1592-1604.

20.    Palmer, R.E., Lee, S.B., Wong, J.C., Reynolds, P.A., Zhang, H., Truong, V., Oliner, J.D., Gerald, W.L., and Haber, D.A.  Induction of BAIAP3 by the EWS-WT1 chimeric fusion implicates regulated exocytosis in tumorigenesis. Cancer Cell 2002; 2:497-505.

21.    Wong, J.C., Lee, S.B., Bell, M.D., Reynolds, P.A., Truong, V., Oliner, J.D., Gerald, W.L., and Haber, D.A.   Induction of the interleukin-2 receptor β-chain by the EWS-WT1 translocation product. Oncogene 2002; 21:2009-2019.

22.    Lee, S.B., Kim, S.H., Bell, D.W., Wahrer, D., Schiripo, T.A., Jorczak, M., Sgroi, D.,Garber, J.E., Li, F.P., Nichols, K., Varley, J.M., Godwin, A.K., Shannon, K.E., Harlow, E., and  Haber, D.A.  Destabilization of CHK2 by a Missense Mutation Associated with Li-Fraumeni Syndrome. Cancer Research 2001; 61:8062-8067.

23.    Lee, S.B., and Haber, D.A.  Wilms Tumor Suppressor WT1.  (Review) Exp. Cell Res. 2001; 264:74-99.

24.    Wang, W., Lee, S.B., Palmer, R., Ellisen, L.W. and Haber, D.A.  A functional interaction with CBP contributes to transactivational activation by the Wilms tumor suppressor WT1.  J. Biol. Chem. 2001; 276:16810-16816.

25.    Haber, D.A., Lee S.B., Ellisen, L.W., Palmer, R., Wong, J., Reynolds, P., and Zhang, H.  The Wilms tumor gene WT1: Searching for function using expression profile analysis. (Review) Clin. Cancer Res. 7 (11): W845 Suppl. S NOV 2001.

26.    Ding, D., Moskowitz, S.I., Li, R., Lee, S.B., Esteban, M., Tomaselli, K., Chan, J., and Bergold, P.J. Acidosis induces necrosis and apoptosis of cultured hippocampal neurons.  Exp. Neurol. 2000; 162(1):1-12.

27.    Lee, S.B., Huang, K., Palmer, R., Troung, V.B., Herzlinger, D., Kolquist, K.A., Wong, J., Paulding, C., Yoon, S.K., Gerald, W., Oliner, J.D., and Haber, D.A.  The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin.  Cell 1999; 98:663-673.

28.    Maheswaran, S., Englert, C., Zheng, G., Lee, S.B., Wong, J., Harkin, P., Bean, J., Ezzell, R., Garvin, A.J., McCluskey, R.T., DeCaprio, J.A., and Haber, D.A.  Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone hsp70.  Genes & Development 1998; 12:1108-1120.

29.    Maheswaran, S., Englert, C., Lee, S.B., Settleman, J., Ezzell, R.M., and Haber, D.A.  The E1B 55K protein product sequesters WT1 along with p53 in adenovirus-transformed cells.  Oncogene 1998; 16:2041-2050.

30.    Lee, S.B., Kolquist, K.A., Nichols, K., Englert, C., Maheswaran, S., Ladanyi, M., Gerald, W.L., and Haber, D.A.  The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour.   Nature Genetics 1997; 17:309-313.

31.    Melkova, Z., Lee, S.B., Rodriguez, D., and Esteban, M.  Bcl-2 prevents nitric oxide-mediated apoptosis and poly(ADP-ribose) polymerase cleavage.  FEBS Lett.1997; 403:273-278.

32.    Lee, S.B., Rodriguez, D., Rodriguez, J-R, and Esteban, M.  The apoptosis pathway triggered by the interferon-induced protein kinase PKR requires the third basic domain, initiates upstream of Bcl-2, and involves ICE-like protease.  Virology 1997; 231:81-88.

33.    Lee, S.B., Bablanian, R., and Esteban, M.  Regulated expression of the interferoninduced protein kinase p68 (PKR) by vaccinia virus recombinants inhibits the replication of the vesicular stomatitis virus but not that of poliovirus.  J. Interferon and Cytokine Res. 1996; 16:1073-1078.

34.    Taylor, D.R., Lee, S.B., Romano, P.R., Marshak, D.R., Hinnebusch, A.G., Esteban, M., and Mathews, M.B.  Autophosphorylation sites participate in the activation of the double-stranded RNA-activated protein kinase PKR.  Mol. Cell. Biol. 1996; 16:6295-6302.

35.    Lee, S.B., and Esteban, M.  The interferon-induced double-stranded RNA-activated protein kinase induces apoptosis.  Virology 1994; 199:491-496.

36.    Lee, S.B., Green, S.R., Mathews, M.B., and Esteban, M.  Activation of the double- stranded RNA-activated human protein kinase in vivo in the absence of its dsRNA binding domain.   Proc. Natl. Acad. Sci. USA   1994; 91:10551-10555.

37.    Lee, S.B., and Esteban, M.  The interferon-induced double-stranded RNA-activated human p68 kinase inhibits the replication of vaccinia virus. Virology 1993; 193:1037-1041.

38.    Lee, S.B., Melkova, Z., Yan, W., Williams, B.R.G., Hovanessian, A.G., and Esteban, M. The interferon-induced double-stranded RNA-activated human p68 protein kinase potently inhibits protein synthesis in cultured cells. Virology 1993; 192:380-385.

Invited Book Chapters:

1.    Lee, S.B., Li, H. and Kim, H.S.  The role of WT1 in Development and Disease.  Chapter 24 in ‘Zinc Finger Proteins’ Edited by Iuchi, S. and Kuldell, N. 2004 Landes Bioscience.

2.    Lee, S.B. Desmoplastic Small Round Cell Tumor. Encyclopedia of Cancer, Second Edition, Edited by Manfred Schwab, 2007 Springer.

Dept. of Pathology & Laboratory Medicine, 1430 Tulane Avenue, New Orleans, LA 70112 504-988-5224 tulpath@tulane.edu