Visiting Associate Professor
Dr. Chen received his undergraduate training at Wuhan University, China in 2003. He 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 as a research assistant professor.
Dr. Chen’s research interests have focused on the role of protein ubiquitination in lung epithelia and cancer pathogenosis throughout many pulmonary diseases. Dr. Chen uses state-of-art tools (FRET, FRAP, two hybrids, microCT scanning) and molecular physiology to assess protein-protein interaction and their relevance to pulmonary physiology. During his doctoral and postdoctoral studies, Dr. Chen performed extensive work investigating the role of calcium activated neutral proteinases and site-specific ubiquitination in regulating key lipogenic proteins in pulmonary surfactant lipid biosynthesis (J Biol Chem. 2007, PMID: 17804406). 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 (Mol Cell Biol 2009, PMID: 19332566). Dr. Chen also discovered during this work that these adverse actions of the E3 ligase are opposed by calmodulin that binds CCTα within a canonical calmodulin binding domain. Calmodulin not only directly binds and stabilizes CCTα, but also directly binds to the ubiquitin E3 ligase, thus neutralizes its action. He demonstrated that calmodulin gene transfer in mice showed significantly improved lung function and less pulmonary edema after infection with P. aeruginosa (Mol Cell Biol 2011, PMID: 21343341).
The following slides showed dual down regulation of phospholipid synthesis in type II cells by the neutral proteinase calpain or ubiquitination system upon cytokine (TNF-α) treatment or P. aeruginosa infection.
The discovery of FBXL2 by Dr. Chen as an authentic ubiquitin E3 ligase subunit led to the identification of multiple FBXL2 substrates in lung epithelia; which regulate not only surfactant synthesis but also cell cycle progression and tumorogenesis. Specifically, FBXL2 expression impaired cell cycle progression by degrading cyclin D3 leading to G2/M arrest leading to tetraploidy (Cell Cycle 2012, PMID: 22024926).
More importantly, ectopic expression of FBXL2 significantly decreased cyclin D3 protein levels, induced apoptosis and inhibited the growth and migration of tumorigenic A549 cells and tumor formation in athymic nude mice which implicate FBXL2 as a regulator of the cell cycle which serves as a tumor suppressor (Oncogene 2012, PMID:22020328). Dr. Chen also discovered that FBXL2 mediates ubiquitination and degradation of cyclin D2 which leads to G0 arrest in B lymphocytes and leukemia cells (Blood 2012, PMID: 22323446).
More recently, he has made other discoveries in the field as he was able to determine yet another novel E3 ligase subunit, termed FBXL7, which ubiquitinates Aurora A and leads to its degradation in the proteasome. Aurora A protein is regulated by FBXL7 within the centrosome during spindle formation. (Cell Cycle 2012 PMID: 22306998).
Agassandian M., Chen, B.B., Pulijala R., Kaercher L., Glasser, J., and Mallampalli, R.K. (2012) Calcium-calmodulin kinase I cooperatively regulates nucleocytoplasmic shuttling of CCTalpha by accessing a nuclear export signal. Mol. Biol. Cell. 23:2755-69
Chen, B.B., Glasser, J.R., Coon, T.A. and Mallampalli, R.K. (2012) FBXL2 mediated cyclin D2 degradation inhibits B lymphocyte proliferation. Blood. 119:3232-41.
Coon, T.A., Glasser, J.R., Mallampalli, R.K. and *Chen, B.B. (2012) Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A causing mitotic arrest. Cell Cycle 11:721-9*corresponding author, cover story.
*Chen, B.B., Glasser, J.R., Coon, T.A. and Mallampalli, R.K. (2011) FBXL2 is a ubiquitin E3 ligase subunit that triggers mitotic arrest. Cell Cycle, 10:3487-94. *corresponding author.
Chen, B.B., Glasser, J.R., Coon, T.A. and Mallampalli, R.K. (2011) F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest. Oncogene 10: p.1038.
Chen, B.B., Coon, T.A., Glasser, J.R., and Mallampalli, R.K. (2011) Calmodulin antagonizes a calcium-activated SCF ubiquitin E3 ligase subunit, FBXL2, to regulate surfactant homeostasis. Mol. Cell Biol. 31:1905-20.
Chen, B.B. and Mallampalli, R.K. Masking of a nuclear signal motif by monoubiquitination leads to mislocalization and degradation of the regulatory enzyme, CCTa. Mol. Cell. Biol. 29:3062-3075, 2009.
Chen, B.B. and Mallampalli, R.K. Calmodulin binds and stabilizes the regulatory enzyme, CTP:phosphocholine cytidylyltransferase. J. Biol. Chem. 282:33494-33506, 2007.