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Department of Medicine

Department of Medicine

  Division of Pulmonary, Allergy and Critical Care Medicine



    Faculty Profile: BEIBEI "BILL" CHEN, PhD LABORATORY LIST  |  FACULTY LIST

Dr. Bill Chen's Research

Dr. Chen’s primary area of research interest is in the study of molecular mechanism of control inflammation and cell proliferation via protein ubiquitination. Specifically, over the last four years, he has successfully cloned over 70 novel ubiquitin E3 ligases, of which he has subsequently determined the substrates of 8 novel E3 ligases. Dr. Chen was the first to characterize an E3 ubiquitin ligase subunit, FBXL2, that targets CCTa (a surfactant producing enzyme), via an IQ motif for monoubiquitination and degradation during Pseudomonas aeruginosa infection. This study demonstrated for the first time that a member of the SCF (Skp1-Cul1-F-box) E3 ligase family which targets a substrate via an IQ motif instead of by the traditional phosphodegron signature. The discovery of FBXL2 by Dr. Chen as an authentic ubiquitin E3 ligase subunit led to the identification of multiple FBXL2 substrates; which regulate not only surfactant synthesis but also cell cycle progression and tumorogenesis. Specifically, FBXL2 expression impaired cell cycle progression by degrading cyclin D2/D3, Aurora B leading to G2/M arrest and tetraploidy. Further, FBXL2 suppresses lung inflammation by targeting the TRAF family of proteins for their disposal in epithelia and monocytes. Dr. Chen’s discovery also includes identification and characterization of an orphan F-box protein, FBXO3, that ubiquitinates and mediates proteasomal degradation of FBXL2, thus FBXO3 indirectly activates TRAF/NF-kb signaling and facilitate sepsis-induced acute lung injury. These findings have led to investigate novel pathways and the biological consequences of mutation or inhibition of FBXO3 in human PBMCs and animal models.

Dr. Chen’s second area of research interest is in the small molecule drug design. He has successfully designed and synthesized a novel series of first-in-class small molecule FBXO3 protein inhibitors. One of his lead compounds BC-1215 is currently undergoing large animal preclinical study. Recently he has also designed a novel series of potent selective PDE4 inhibitors derived from traditional Chinese medicine Forsythia. His long-term goal is to develop a new class of therapeutics to combat inflammatory diseases focusing on a novel mechanism.


SCFFbxl2 complex targets many substrates for ubiquitination. Calmodulin (CaM) antagonizes the process by interrupt the interaction between FBXL2 and the substrates. FBXO3 protects the downstream substrates by ubiquitinating FBXL2.