Associate Professor of Medicine
Dr. Beibei (Bill) Chen is currently an associate professor within the Acute Lung Injury Center of Excellence (ALI center). He received his undergraduate training at Wuhan University, China in 2003. After working in pharmaceutical industry for a year, he moved to Iowa and received his Ph.D. in Biochemistry from the University of Iowa in 2008 studying the molecular control of phosphatidylcholine (PC) synthesis as it relates to sepsis–induced acute lung injury. He continued this area of study under the mentorship of Rama Mallampalli M.D. for his post-doctoral training. In Sept. 2009, Dr. Chen joined the Pulmonary, Allergy, and Critical Care faculty at the University of Pittsburgh.
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.
The ApaG Fbxo3 domain serves as a target for small molecules. A. Several deletion mutants of Fbxo3 were designed and cloned into a pcDNA3.1D/V5-HIS vector. B. In vitro ubiquitination assays. Purified SCFFbxo3 full-length (FL) or truncated Fbxo3 proteins were incubated with V5-Fbxl2 substrate and the full complement of ubiquitination reaction components showing polyubiquitinated Fbxl2 (second lane from left). C. Structural analysis of the Fbxo3-ApaG domain showing highly conserved bacterial (left) and mammalian Fbxo3 (second from left) structures. D. Structure of the BC-1215/ApaG complex. Green: BC-1215. E. Human peripheral blood mononuclear (PBMC) cells were treated with LPS (2 mg/ml) for 16 h along with either benzathine or several candidate compounds at different concentrations and IL1b monitored to calculate the IC50. For LD50, U937 monocytes were treated with the small molecules at different concentrations for 16 h. Cells were then stained with trypan blue to identify dead cells, and to calculate the LD50.
Chen BB, Coon TA, Glasser JR, Zou C, Ellis B, Kamga C, Shiva S, Mallampalli RK. E3 ligase FBXO15 and kinase PINK1 regulate Cardiolipin Synthase (CLS1) stability and mitochondrial function. Cell Reports. (In press).
Mallampalli RK, Coon TA, Glasser JR, Wang C, Dunn SR, Weathington, NM, Zhao J, Zou C, Zhao Y, Chen BB. Targeting F box protein Fbxo3 to control cytokine-driven inflammation. J Immunol. 2013 Nov 15;191(10):5247-55. doi: 10.4049/jmmunol.1300456. [Epub 2013 Oct 11.] *corresponding author. PMCID: PMC3845358.
Chen BB, Glasser JR, Coon TA, Mallampalli RK. Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis. Cell Death Dis. 2013 Aug 8;4e759. doi:10.1038/cddis.2013.271. PMCID: PMC3763433.
Mallampalli RK, Glasser JR, Coon TA, Chen BB. Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis. Cell Cycle. 2013 Feb 15;12(4):663-73. doi: 10.4161/cc.23586. [Epub 2013 Jan 31.] PMCID: PMC3594267.
Chen BB, Coon TA, Glasser JR, McVerry BJ, Zhao J, Zhao Y, Zou C, Ellis BM, Sciurba FC, Zhang Y, Mallampalli RK. A combinatorial F box protein directed pathway controls TRAF stability to regulate inflammation. Nat Immunol. 2013 Mar 31. doi: 10.1038/ni.2565. [Epub ahead of print] PMCID: PMC3631463. Highlighted in Nat Rev Immunol and Nat Rev Drug Design.
Chen BB, Mallampalli RK. F-box protein substrate recognition: A new insight. Cell Cycle 2013 Apr 1;12(7):1009-10. doi: 10.4161/cc.23071. [Epub 2012 Dec 19.] PMID: 23255120; PMCID: PMC3646851
Chen BB, Glasser JR, Coon TA, Zou C, Miller HL, Fenton M, McDyer JF, Boyiadzis M, Mallampalli RK. F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Blood. 2012 Mar 29;119(13):3132-41. doi: 10.1182/blood-2011-06-358911. [Epub 2012 Feb 8.] PMID: 22323446; PMCID: PMC3321873
Coon TA, Glasser JR, Mallampalli RK, Chen BB. Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A, causing mitotic arrest. Cell Cycle.2012 Feb 15;11(4):721-9. doi: 10.4161/cc.11.4.19171. [Epub 2012 Feb 15.], cover story. PMID: 22306998; PMCID: PMC3318106