Professor, Department of Biochemistry, Yong Loo Lin School of Medicine, NUS.
Professor, Department of Biological Sciences, Faculty of Sciences, NUS.
Senior Principal Investigator, Cancer Stem Cells Programme, Cancer Science Institute of Singapore.
Supervisor, NUS Graduate School for Integrative Sciences and Engineering (NGS), NUS.
|Degree and Institution
|Postdoctoral: Rockefeller University New York, USA
|Ph.D. Molecular Biology from Columbia University
|Director of International Relation (China), Yong Loo Lin School of Medicine, National University of Singapore
|Professor, Department of Biochemistry,Yong Loo Lin School of Medicine, National University of Singapore
|Senior Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore
|Head, Department of Biochemistry,Yong Loo Lin School of Medicine, National University of Singapore
|Professor, Microbiol and Immunology, Indiana University School of Medicine
|Associate Professor, Member, Yale Cancer Center, Yale University, New Haven, CT
|Assistant Professor, Pathology, Yale University School of Medicine
|Assistant Professor, Mount Sinai School of Medicine, New York
* Molecular mechanisms of STAT3 in regulation of tumorigensis, metastasis and angiogenesis
* The key functions of STAT proteins in epigenetic regulation of stem cells, development and diseases
* Reprogramming mechanisms during early development and generation of adult stem cells
* Mechanisms of neural development, gene circuitry for formation of cognition and related diseases
In particular, we are pursuing the following projects:
1) To investigate the critical roles of endothelial STAT3 in tumour angiogenesis. We have created an endothelial cell (EC)-specific deletion in STAT3 (STAT3E–/– for ECs) to study the pathophysiological functions of EC-expressed STAT3 in vivo. Possible epigenetic alterations induced by STAT3 activity will be examined.
2) To reveal the molecular mechanisms of tumour metastasis and the role of STAT3 during this process. Tumour metastasis involves invasion; tumour cell dissemination through blood vessels or the lymphatic system; colonization of distant organs; and, finally, the outgrowth of metastases. We are investigating the possible molecular bases responsible for this STAT3 mediated metastasis.
3) A novel direction of the lab is to investigate whether tumourigenesis can be affected via inflammation regulated by STAT3. We are investigating a hypothesis that STAT3, as an oncogene, can regulate epigenetic factors during T helper cell-mediated inflammation and cause tumourigenesis. We plan to systematically investigate the manner in which inflammatory responses cause epigenetic alterations and to study their effects on cancer development.
4) The regulatory roles of STAT proteins in stem cells. In my laboratory, we have recently developed systems using Embryonic Stem (ES) cells and Induced Pluripotent Stem (iPS) cells. We have established different in vitro developmental systems particularly in neurogenesis and hematopoiesis. The objectives are to reveal epigenetic mechanisms that are controlled through STAT signaling to specific gene regulatory circuitries.
Fu, X.-Y, Schindler, C., Improta, T., Aebersold, R. and Darnell, J. E.(1992) The proteins of ISGF3, the IFN-alpha induced transcriptional activator, define a gene family involved in signal transdution. Proc. Natl. Acad. Sci. USA, 89:7840-7843. (This paper described original cloning of the first two STAT genes).
Fu, X.-Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferon-alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24; 70(2):323-335. (This paper described original discovery of the mechanism of STAT signaling pathway).
Fu, X.-Y and Zhang JJ. Transcription factor p91 interacts with the EGF receptor and mediates activation of the c-fos gene promoter. Cell. 1993 Sep 24, 74(6):1135-1145.
Chin EY, Kitagawa M, Su WS, You ZH, Iwamoto Y and Fu, X.-Y. Cell Growth Arrest and Induction of Cyclin Dependent Kinase Inhibitor p21WAF1/CIP1 Mediated by STAT1. Science. 1996 May 3; 272(5262):719-22.
Su WCS, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, Deng C, Horton WA and Fu, X.-Y. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature. 1997 Mar 20; 386(6622):288-92.
Welte T, Leitenberg D, Dittel BN, al-Ramadi BK, Xie B, Chin YE, Janeway CA, Bothwell AL, Bottomly K, Fu, X.-Y. STAT5 interaction with the T cell receptor complex and stimulation of T cell proliferation. Science. 1999 Jan 8; 283(5399):222-5.
Welte T, Zhang SS, Wang T, Zhang Z, Hesslein DG, Yin Z, Kano A, Iwamoto Y, Li E, Craft JE, Bothwell AL, Fikrig E, Koni PA, Flavell RA, Fu, X.-Y. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A. 2003 Feb 18; 100(4):1879-84.
Kano, A., Wolfgang, M., Gao, Q., Zhang, S. S-M. Iwamoto, Y., Pober, J., Flavell, R. A. and Fu, X.-Y. (2003) Endothelial cells require Stat3 for protection against endotoxin-induced inflammation Journal of Experimental Medicine, 198, 1517-1525.
Laouar*, Y., Welte*, Fu, X.-Y.** and Flavell, R. A. (2003) Flt3 ligand specifically requires Stat3 in the induction of dendritic cell development from hematopoietic stem cells Immunity, 19, 849–861. *These authors contribute equally to this work. ** The Corresponding Author.
Gao Q, Wolfgang MJ, Neschen S, Katsutaro Morino, Tamas L. Horvath, Shulman G, & Fu, X.-Y. (2004). Disruption of Neural Stat3 Causes Obesity, Diabetes, Infertility and Thermal Dysregulation Proc. Natl. Aca. Sci. USA 101, 4661–4666.
Liu, L, Song, L., Yu, X-Z., Li, T. S., Li, Z. G., Chen, P. L., Li, Y. H.,, Wang, S. D. ., Chen, Y., Chang, Z. J. and Fu, X.-Y. (2004) A novel protein tyrosine kinase NOK that shares homology with PDGF/FGF receptors, induces tumorigenesis and metastasis in nude mice. Cancer Research 64, 3491-3499.
Chow, EK, O’Connell, R.M., Schilling, S., Wang, X. F., Fu, X.-Y. and Cheng G., (2005) TLR agonists regulate PDGF-B production and cell proliferation through TGF-b/type I IFN crosstalk. EMBO J, 24, 4071–4081.
Rong Y, Cheng L, Chang Z, and Fu, X.-Y. WT1 and STAT3 synergistically promote cell proliferation: A possible mechanism in sporadic Wilms' tumor. Cancer Research. 2006 Aug 15; 66(16):8049-57.
Kim BG, Li C, Qiao W, Mamura W, Kasperczak B, Anver M, Wolfraim L, Hong S, Mushinski E, Kim SG, Fu, X.-Y, Deng C and Letterio JJ. SMAD4 signaling in T cells is required for suppression of gastrointestinal cancer. Nature 2006 Jun 22; 441(7096):1015-9.
Wang M, Zhang W, Crisostomo P, Markel T, Meldrum KK, Fu, X.-Y, Meldrum DR. (2007) Endothelial STAT3 plays a critical role in generalized myocardial proinflammatory and proapoptotic signaling. Am J Physiol Heart Circ Physiol. 293(4):H2101-8. Epub 2007 Aug 3.
Moh, A., Zhang, W., Wang, Z., Wang, J. and Fu, X.-Y (2008) STAT3 sensitizes insulin signaling by negatively regulating GSK-3β. Diabetes. 57(5):1227-35. Epub 2008 Feb 11.
Cohen P. A., Koski, G.K., Czerniecki, B.J., Bunting, K.D., Fu, X.-Y, Wang, Z., Zhang W.J. et al., (2008) STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells. Blood, 112(5):1832-43. Epub 2008 Jun 24.
Wegrzyn, J., Potla, R., Chwae, Y-J, Fu, X.-Y., Larner, A. C etc (2008) A Novel Function of Stat3 in Cellular Respiration. Science, 323(5915): 793-7. Epub 2009 Jan 8. 5).
Zhang W, Chan RJ, Chen H, Yang Z, He Y, Zhang X, Luo Y, Yin F, Moh A, Miller LC, Payne RM, Zhang ZY, Fu, X.-Y, Shou W. (2009) Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. J Biol Chem. 284(33):22353-63. Epub 2009 Jun 9.
Fukuda S, Singh P, Moh A, Abe M, Conway EM, Boswell HS, Yamaguchi S, Fu, X.-Y, Pelus LM. Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal-tandem-duplication of Flt3. (2009) Blood. 114(2):394-403.
Wang, H, O Park, F Lafdil, K Shen, N Horiguchi, S Yin, X-Y FU, G Kunos and B Gao, "Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity". HEPATOLOGY, 51, no. 4 (2010): 1354-1362. (United States). (PMID: 20041412).
Charlie Mantel, Steven Messina-Graham, Akira Moh, Scott Cooper, Giao Hangoc, Xin-Yuan Fu, and Hal E. Broxmeyer. (2012) Hematopoietic cell-targeted STAT3 Deletion: Stem/Progenitor Cell
Defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype. Blood, 120(13):2589-99. Epub 2012 Jun 4
Dang Vinh Do, Jun Ueda, Chanchao Lorthongpanich, Wenjun Zhang , Akira Moh , Yi Zhou, Bo Feng, Guoji Guo, Peiyu J Lin, Md Zakir Hossain, Daniel M. Messerschmidt , Qiang Wu, Paul Robson, Huck Hui Ng, Lorenz Poellinger, Barbara B. Knowles, Davor Solter and Xin-Yuan Fu. A Genetic and Developmental Pathway from STAT3 to the OCT4-NANOG Circuit Essential for Maintenance of ICM Lineages in vivo. Genes & Development, 2013 Jun 15;27(12):1378-90. doi: 10.1101/gad.221176.113.PMID: 23788624