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Tulane University Health Sciences
Department of Pathology and Laboratory Medicine
1430 Tulane Avenue SL-79
New Orleans, Louisiana
70112-2699
Phone 504-988-5224
Fax 504-988-7389
Email tulpath@tulane.edu

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

Peer-reviewed publications:

1.  Lee, S.B., Melkova, Z., Yan, W., Williams, B.R.G., Hovanessian, A.G., and Esteban, M. (1993). The interferon-induced double-stranded RNA-activated human p68 protein kinase potently inhibits protein synthesis in cultured cells. Virology 192:380-385. PMID: 7685968.

2.  Lee, S.B., and Esteban, M. (1993). The interferon-induced double-stranded RNA-activated human p68 kinase inhibits the replication of vaccinia virus. Virology 193:1037-1041. PMID: 8096351.

3.  Lee, S.B., Green, S.R., Mathews, M.B., and Esteban, M. (1994). 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 91:10551-10555. PMID: 7937992.

4.  Lee, S.B., and Esteban, M. (1994). The interferon-induced double-stranded RNA-activated protein kinase induces apoptosis.Virology 199:491-496. PMID: 7510087.

5. Taylor, D.R., Lee, S.B., Romano, P.R., Marshak, D.R., Hinnebusch, A.G., Esteban, M., and Mathews, M.B. (1996). Autophosphorylation sites participate in the activation of the double-stranded RNA-activated protein kinase PKR.Mol. Cell. Biol. 16:6295-6302. PMID: 8887659.

6. Lee, S.B., Bablanian, R., and Esteban, M. (1996). 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.16:1073-1078. PMID: 8974011.

7.  Lee, S.B., Rodriguez, D., Rodriguez, J-R, and Esteban, M. (1997). 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 231:81-88. PMID: 9143305.

8. Melkova, Z., Lee, S.B., Rodriguez, D., and Esteban, M. (1997). Bcl-2 prevents nitric oxide-mediated apoptosis and poly(ADP-ribose) polymerase cleavage.FEBS Letter 403:273-278. PMID: 9091316.

9. Lee, S.B., Kolquist, K.A., Nichols, K., Englert, C., Maheswaran, S., Ladanyi, M., Gerald, W.L., and Haber, D.A. (1997). The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour.Nature Genetics 17:309-313. PMID: 9354795.

10. Maheswaran, S., Englert, C., Lee, S.B., Settleman, J., Ezzell, R.M., and Haber, D.A. (1998). The E1B 55K protein product sequesters WT1 along with p53 in adenovirus-transformed cells.Oncogene 16:2041-2050. PMID: 9572485

11. 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. (1998). Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone hsp70.Genes & Development 12:1108-1120. PMID: 9553041.

12.  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. (1999). The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin.Cell 98:663-673. PMID: 10490105.

13. Ding, D., Moskowitz, S.I., Li, R., Lee, S.B., Esteban, M., Tomaselli, K., Chan, J., and Bergold, P.J. (2000). Acidosis induces necrosis and apoptosis of cultured hippocampal neurons.Exp. Neurol. 162(1):1-12. PMID: 10716884.

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

15. Wang, W., Lee, S.B., Palmer, R., Ellisen, L.W. and Haber, D.A. (2001). A functional interaction with CBP contributes to transactivational activation by the Wilms tumor suppressor WT1.J. Biol. Chem. 276:16810-16816. PMID: 11278547.

16.  Lee, S.B., and Haber, D.A. (2001). Wilms Tumor Suppressor WT1. (Review) Exp. Cell Res. 264:74-99. PMID: 11237525.

17.  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., andHaber, D.A. (2001). Destabilization of CHK2 by a Missense Mutation Associated with Li-Fraumeni Syndrome. Cancer Research 61:8062-8067. PMID: 11719428.

18. Wong, J.C., Lee, S.B., Bell, M.D., Reynolds, P.A., Truong, V., Oliner, J.D., Gerald, W.L., and Haber, D.A. (2002). Induction of the interleukin-2 receptor -chain by the EWS-WT1 translocation product. Oncogene 21:2009-2019. PMID: 11960373.

19. 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. (2002). Induction of BAIAP3 by the EWS-WT1 chimeric fusion implicates regulated exocytosis in tumorigenesis. Cancer Cell, 2:497-505. PMID: 12498718.

20. 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.(2003). P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells. Genes & Development 17:1592-1604. PMID: 12842911.

21. Shao, J., Lee, S.B., Guo, H., Evers, B.M., and Sheng, H.(2003). Prostaglandin E2 stimulates the growth of colon cancer cells via induction of amphiregulin.Cancer Research 63(17):5218-23. PMID: 14500348.

22. 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. (2004). A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus.J Biol Chem. 279(14):14398-14408. PMID: 14736876.

23. O'Reilly, S.M., Leonard, M.O., Pouliot, M., Lee, S.B., and Taylor, C.T. (2006). Hypoxia induces intestinal epithelial amphiregulin gene expression in a CREB-dependent manner. Am. J Physiol. Cell Physiol. 290: C592-C600. PMID: 16207795.

24. 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. (2006). Oncoprotein EWS-FLI1 Activity Is Enhanced by RNA Helicase A. Cancer Research 66:5574-5581. PMID: 16740692.

25. Kim, H.S., Li, H., Cevher, M., Parmelee, A., Fonseca, D., Kleiman, F.E., and Lee, S.B. (2006). DNA damage-induced BARD1 phosphorylation is critical for the inhibition of pre-mRNA processing by BRCA1/BARD1 complex. Cancer Research 66:4561-4565. PMID: 16651405.

26. 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. (2007). Identification of novel WT1 target genes implicated in kidney development. J Biol. Chem. 282:16278-16287. PMID: 17430890.

27. Li, H., Watford, W., Li, C., Parmelee, A., Bryant, M.A., Deng, C., O'shea, J., and Lee, S.B. (2007). Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development. J. Clinical Investigation 117:1314-1323. PMID: 17415412. (*Selected by F1000 Prime as being of special significance in its field)

28. Li, H., Smolen, G.A., Beers, L.F., Xia, L., Gerald, W., Wang, J., Haber, D.A., and Lee, S.B. (2008). Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in Desmoplastic Small Round Cell Tumor. PLoS One 3(6):e2353. PMID: 18523561.

29.  Choi, J., Oh, S., Lee, D., Oh, H.J., Park, J.Y., Lee, S.B. and Lim, D.S. (2009).Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice. PLoS One4(11): e8011. PMID: 19956688.

30.  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. (2009). Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor. PLoS Genetics5(11): e1000745. PMID: 19956686.

31. Sohn, E.J., Li, H., Reidy, K., Beers, L.F., Christensen, B.L. and Lee, S. B. (2010). EWS/FLI1 Oncogene Activates Caspase 3 Transcription and Triggers Apoptosis In Vivo. Cancer Research 70:1154-1163. PMID: 20103643.

32. 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.(2010). A Novel Wilms Tumor 1 (WT1) Target Gene Negatively Regulates the WNT Signaling Pathway. J. Biol. Chem. 285:14585-14593. PMID: 20220130.

33. 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.(2010). SOX4 Overexpression Regulates the p53-mediated Apoptosis in Hepatocellular Carcinoma: Clinical Implication and Functional Analysis in vitro. Carcinogenesis 31:1298-1307. PMID: 20400479.

34. Cevher M.A., Zhang, X., Fernandez, S., Kim, S., Baquero, J., Nilsson, P., Lee, S.B., Virtanen, A., Kleiman, F.E. (2010). Nuclear deadenylation/polyadenylation factors regulate 3' processing in response to DNA damage. EMBO J. 29:1674-87. PMID: 20379136.

35. 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. (2010). Tumor Suppressor Ras-Association Domain Family 5 (RASSF5/NORE1) Mediates TNF-a Induced Apoptosis. J. Biol. Chem. 285:35029-35038. PMID: 20810663.

36. Cho, J., Shen, H., Yu, H., Li, H., Cheng, T., Lee, S.B. and Lee, B.C. (2011). Ewing's sarcoma gene EWS regulates hematopoietic stem cell senescence. Blood 117:1156-1166. PMID: 21030557.

37. Park, B.H., Lee, S.B., Stolz, D. B., Lee, Y.J. and Lee, B.C. (2011). Synergistic interactions between heregulin and peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist in breast cancer cells. J. Biol. Chem. 286:20087-20099. PMID: 21467033.

38. 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. (2012). Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1. EMBO Reports 13:163-169. PMID: 22173032.

39. Kook, S.H., Cho, J., Morrison, A., Wiener, E., Lee, S.B., Scadden, D. and Lee, B.C. (2013). The purinergic P2Y14 receptor axis is a molecular determinant for organism survival under un utero radiation toxicity. Cell Death & Disease 4:e703. PMID: 23828566.

40. Kook, S.H., Cho, J., Lee, S.B. and Lee, B.C. (2013). A nucleotide sugar, UDP-Glucose, is a novel mobilizer of long-term repopulating primitive hematopoietic cells. J. Clinical Investigation 123:3420-3435. PMID: 23863713.

41. Park, B.H., Kook, S., Lee, S.B., Jeong, J.H., Brufsky, A. and Lee, B.C. (2013). An isoform of C/EBP beta, LIP, regulates expression of the chemokine receptor CXCR4 and modulates breast cancer cell migration. J. Biol.Chem. 288:28656-28667. PMID: 23966000.

42. Gordon, M., El-Kalla, M., Zhao, Y., Fiteih, Y., Law, J., Volodko, N., Mohamed, A., El-Kadi, A. O., Liu, L., Odenbach, J., Thiesen, A., Onyskiw, C., Ghazaleh, H. A., Park, J., Lee, S. B., Yu, V. C., Fernandez-Patron, C., Alexander, R. T., Wine, E., and Baksh, S. (2013). The tumor suppressor gene, RASSF1A, is essential for protection against inflammation-induced injury. PLoS One 8, e75483. PMID: 24146755.

43. Park, J.H., Kang, H.J., Kang, S.I., Lee, J.E., Hur, J., Ge, K., Mueller, E., Li, H., Lee, B.C. and Lee, S.B. (2013). A multifunctional protein EWS is essential for early brown fat lineage determination. Developmental Cell 26:393-404. PMID: 23987512. (*Selected by F1000 Prime as being of special significance in its field)

44. Kim, K. Y., Hwang, Y. J., Jung, M. K., Choe, J., Kim, Y., Kim, S., Lee, C. J., Ahn, H., Lee, J., Kowall, N. W., Kim, Y. K., Kim, J. I., Lee, S. B., and Ryu, H. (2014). A multifunctional protein EWS regulates the expression of Drosha and microRNAs. Cell Death Differentiation 21:136-145. PMID: 24185621.

45. Kang, H.J., Park, J.H., Chen, W., Kang, S.I., Moroz, K., Ladanyi, M. and Lee, S.B. (2014). EWS-WT1 oncoprotein activates neural reprogramming factor ASCL1 and promotes neural differentiation. Cancer Research 74:4526-4535. PMID: 24934812.

46. Park, J.H. and Lee, S.B. (2015). An essential role for Ewing sarcoma gene, EWS, in early white adipogenesis. Obesity 23:138-144. PMID: 25407167.

47. Park, J.H., Kang, H.J., Lee, Y.K., Kang, H., Kim, J., Chung, J.H., Chang, J.S., McPherron, A.C. and Lee, S.B. (2015). Inactivation of EWS reduces PGC-1a protein stability and mitochondrial homeostasis. Proc. Natl. Acad. Sci. USA 112:6074-6079. PMID: 25918410.

48. Kim, Y., Kim, K.Y., Jung, M.K., Hwang, Y.J., Kim, S., Lee, C.J., Ko, S., Kowall, N.W., Lee, S.B., Lee, J. and Ryu, H. (2015). UVRAG targeting by miR-125a and miR-351 modulates autophagy associated with EWS deficiency. Autophagy 11:796-811. PMID: 25946189.

49. Park, J.H., Hur, W. and Lee, S.B. (2015). Intricate transcriptional networks of classical brown and beige fat cells. (Invited Review) Frontiers in Endocrinology 6:124. PMID: 26322018.

50. Minas, T., Surdez, D., Taheresh, J., Tanaka, M., Howarth, M., Kang, H.J., Han, J., Han, Z-Y., Sax, B., Kream, B.E., Hong, S-H., Tirode, F., Tuckermann, J., Toretsky, J., Kenner, L., Kovar, H., Lee, S.B.*, Sweet-Cordero*, A., Nakamura, T.*, Moriggl, R.*, Delattre, O.* and Uren, A.* (2016). Combined experience of six independent laboratories attempting to create Ewing sarcoma mouse model. Oncotarget epub (*Co-corresponding author). PMID: 27191748.

51. Lee, C.J., Ahn, H., Lee, S.B. Shin, J.Y., Park, W.Y., Kim, J.I., Lee, J., Ryu, H. and Kim, S. (2016). Integrated analysis of omics data using microRNA-target mRNA network and PPI network reveals regulation of Gnai1 function in the spinal cord of Ews/Ewsr1 KO mice. BMC Medical Genomics 9(Suppl 1):33. PMID: 27534535.

52. Lee, J., Hwang, Y.J., Chung, A.J., Lee, W.C., Kim, Y.H., Jang, S.J., Kowall, N.W., Kim, J.I., Park, H.C., Lee, S.B.* and Ryu, H.* (2016). Ewsr1 deficiency impairs motor neuron development and axon myelination by deregulating oligodendrocyte gene expression. Brain epub (*Co-corresponding author). PMID:

Book chapters:

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

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

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