Yuan Chen, Ph.D.
- Professor, Department of Molecular Medicine
Yuan Chen, Ph.D.
- Cancer Biology
- Molecular Medicine
- Ph.D., Rutgers University
- Scripps Research Institute
Our current research interest is in protein modifications by a family of small proteins known as ubiquitin and its homologues. These modifications control life spans, trafficking, assembly and enzymatic activities of cellular proteins, and are important in nearly every aspect of biological functions. We employ a combination of structural, biochemical, molecular and cellular biological methods to understand these processes in cellular regulation and disease pathogenesis. Specific areas of interest are outlined below.
The Role of SUMOylation in Oncogenesis
Post-translational modifications by the small ubiquitin-like modifiers (SUMO) are important in oncogenesis and cellular response to DNA damage. Recent findings indicate that the key oncogenic pathways driven by Myc and KRas are dependent on, or addicted to, SUMOylation. For example, knocking down of the gene encoding the catalytic subunit of the SUMO activating enzyme (SAE), SAE2, has the strongest synthetic lethal interaction with Myc hyperactivation. We are investigating the molecular mechanisms underlying the synthetic lethality of SUMOylation with Myc hyperactivation and KRas mutations. In addition, we are investigating the structure-activity relationship of how the inhibitors interact with the SAE and inhibit its enzymatic activity, and use this information to guide further improvement of the inhibitors. These studies could potentially improve treatment of many cancers, as overexpression of Myc is estimated to contribute to 70 percent of all human cancers, and KRas is also frequently mutated in human cancers.
SUMO Modifications and HIV Replication
SUMO-specific proteases (SENP) regulate post-translational modifications by SUMO through catalyzing the maturation of SUMO precursors and the removal of SUMO from modified proteins. Small molecule inhibitors of SENPs that function in cells would be valuable tools for elucidating the functions of SENPs. We have recently identified a family of small molecule inhibitors of SENPs that inhibit de-SUMOylation activities in cells. Coincidently, these small molecules had been shown to confer anti-HIV activities in a National Cancer Institute antiviral screen, although the cellular targets and the mechanism of inhibition of HIV were unknown. We are investigating the molecular mechanism of how SUMOylation is involved in HIV life cycle. In addition, we are conducting the structure-activity relationship studies of how these inhibitors interact with the SENPs and inhibit their enzymatic activity, and use this information to develop improved inhibitors. Furthermore, we are interested in exploiting this pathway to develop a potential strategy for a cure of HIV by allowing the immune system to target HIV infected cells without producing infectious virus.
Metabolic activity is a reflection of cellular functions. Our laboratory utilizes nuclear magnetic resonance (NMR) spectroscopy as tools for metabolomic studies, that is, global analysis of metabolic activities. Our goal is to provide information on cellular pathways to understand metabolic dysfunctions of cancer cells.
Application of NMR Methods in Drug Discovery
We are collaborating with several other laboratories with expertise in synthetic chemistry, molecular biology and medical oncology to develop new therapeutics for cancer. State-of-the-art NMR methods are employed to provide information on protein-ligand interactions at an atomic resolution; information that is critical for the rational design of new therapeutics.
Gold nanoparticles as a platform for creating a multivalent poly-SUMO chain inhibitor that also augments ionizing radiation
YJ Li, AL Perkins, Y Su, Y Ma, L Colson, DA Horne, Y Chen
Proceedings of the National Academy of Sciences 109 (11), 4092-4097, 2012
The intrinsic affinity between E2 and the Cys domain of E1 in ubiquitin-like modifications
J Wang, W Hu, S Cai, B Lee, J Song, Y Chen
Molecular cell 27 (2), 228-237, 2007
Identification of a SUMO-binding motif that recognizes SUMO-modified proteins
Jing Song, Linda K Durrin, Thomas A Wilkinson, Theodore G Krontiris, Yuan Chen
Proceedings of the National Academy of Sciences of the United States of America, 101 (40), 14373-14378, 2004
More publications available here.
Facilities & Licensing Information:
Computers and Software
- Six Linex workstations
- Two multi-processor servers
- Software include: InsightII, FELIX, NMRVIEW, NMRDRAW, PIPE, MOLMOL, DYANA, CNS, ARIA, HADDOCK and AMBER.
Other Shared Equipment
- Isothermal titration calorimeter
- Jasco CD instrument
- Automated Applied Biosystems (AB) Procise Protein Sequencing System for N-terminal Edman degradation
- A Perkin Applied Biosystems Procise C-terminal sequencer and a Hewlett Packard C-terminal sequencer
- Dionex AAA Direct amino acid analyzer
- HPLC systems suitable for narrow-bore and microcapillary chromatography and equipped for detection of peptides at 214 nm as well as variable wavelength fluorescence detection
- Pharmacia FPLC for protein purification
- Perkin-Elmer FTIR
- Hitachi UV/VIS Spectrophotometer
- Pharmacia BIAcoreTM System
- PerSeptive Biosystems BioCAD/SPRINT
- Bio-Rad scanning Densitometer
- Three Thermo Finnigan LCQ family ion traps (two Classic and one Deca) equipped with electrospray/LC sources.
- An Applied Biosystems Mariner electrospray (ES) Orthogonal TOF spectrometer
- Applied Biosystems Voyager DE STR MALDI-TOF spectrometer
- Scintillation and gamma counters
- Wallac Micro Beta counter
For more information on licensing, please contact Matthew Grunseth, M.B.S., Technology Licensing Manager, at [email protected].
Chih-Hong Chen, Ph.D.