|Department Affiliations||Departments of Biochemistry & Molecular Biology, JHSPH, Concology, SOM|
|SOM Address||W8025 Bloomber School of Public Health Building|
Nuclear factor kappaB (NF-B) is a pleiotropic transcription factor that involves with diverse biological activities. Aberrant NF-B signaling has known to be associated with cancer and inflammatory diseases; therefore the NF-B pathway has long served as an avenue for drug discovery and development. However, the promoter selectivity and regulatory specificity of NF-B remains largely unknown. Our recent work demonstrated a new regulatory paradigm of NF-B activation in which DNA binding activity could be regulated within NF-B complexes through synergistic interaction between Rel and non-Rel subunits, thus shedding new insights into the specificity of NF-B gene transcription. More important, these non-Rel subunits are over-expressed in certain types of tumors, and modulated by bacterial pathogens during infections, suggesting that they could play critical roles in tumorigenesis and inflammation. Our laboratory will combine biochemical, molecular, cellular and genetic approaches to investigate the mechanism and the pathophysiological significance of the non-Rel subunits-conferred regulatory specificity of NF-B in colonic pathogen infection, inflammation, and cancer. Key questions are what is the molecular mechanism of the non-Rel subunits-conferred specific recognition of double-stranded DNA; what are the modulations of these non-Rel subunits during NF-B activation; what are the roles of these non-Rel subunits and their modulations in colonic pathogen infection, inflammation and tumorigenesis; and how this knowledge can be used for therapeutic treatment of cancer and inflammatory diseases. In addition, we are also studying the regulation of T cell functions in the pathogenesis of autoimmune inflammation in the central nervous system (CNS), using the experimental autoimmune encephalomyelitis (EAE), a mouse model for human disease multiple sclerosis (MS).
• Kai Fu, Xin Sun, Wenxin Zheng, Eric M. Wier, Andrea Hodgson, Dat Q. Tran, Stephane Richard, and Fengyi Wan (2013) Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells. Nat Commun. 4: 1909
• Eric M. Wier, Jordan Neighoff, Xin Sun, Kai Fu, and Fengyi Wan (2012) Identification of an N-terminal truncation of the NF-κB p65 subunit that specifically modulates ribosomal protein S3-dependent NF-κB gene expression. J Biol Chem. 287 (51): 43019-43029
• Fengyi Wan, Amanda Weaver, Xiaofei Gao, Michael Bern, Philip R. Hardwidge, and Michael J. Lenardo (2011) IKK phosphorylation regulates RPS3 nuclear translocation and NF-B function during infection with Escherichia coli strain O157:H7. Nat Immunol. 12 (4): 335-343
• Fengyi Wan and Michael J. Lenardo (2010) The nuclear signaling of NF-B: Current knowledge, new insights, and future perspectives. Cell Res. 20 (1): 24-33
• Fengyi Wan, D. Eric Anderson, Robert A. Barnitz, Andrew Snow, Nicolas Bidere, Lixin Zheng, Vijay Hegde, Lloyd T. Lam, Louis M. Staudt, David Levens, Walter A. Deutsch and Michael J. Lenardo (2007) Ribosomal Protein S3: A KH Domain Subunit in NF-B Complexes that Mediates Selective Gene Regulation. Cell 131(5): 927-939
• Zhou W, Jubb AM, Lyle K, Xiao Q, Ong CC, Desai R, Fu L, Gnad F, Song Q, Haverty PM, Aust D, Grützmann R, Romero M, Totpal K, Neve RM, Yan Y, Forrest WF, Wang Y, Raja R, Pilarsky C, de Jesus-Acosta A, Belvin M, Friedman LS, Merchant M, Jaffee EM, Zheng L, Koeppen J, Hoeflich KP. PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition. Journal of Pathology 2014 Jul 30.