My lab focuses on cancer relevant E3 ligases, a class of enzymes that regulate protein degradation of key oncoproteins and tumor suppressors. Identification of such E3 ligases and understanding of their mechanisms of action will pave a way for screening of small molecule compounds as novel therapies for cancer. We are using biochemical purification approach for identification of new E3 ligases.
Biochemistry also helped us understand how Mdm2-MdmX E3 complex regulates p53. Based on our findings, we are trying to understand how Mdm2-MdmX complex contribute to cancer development in p53-dependent and p53-independent manner and to explore targeting Mdm2-MdmX E3 complex as a new strategy for p53 restoration in cancer therapy. NEDD4-1 E3 ligase is another focus of the lab since we found that NEDD4-1 is involved in regulating PTEN, pAKT and Mdm2.
With a FRET-based high throughput screening assay established in the lab, we are screening small molecule inhibitors for cancer-relevant E3 ligases with a goal of developing a class of novel therapeutic agents for targeted therapies of cancer.
In collaboration with Dr. Fengzhi Li, we identified a new mechanism of action for FL118, a novel camptothecin analog in MdmX degradation and induction of p53-dependent senescence as one of its anticancer mechanisms. These findings allow us to test mechanism-based combination therapies using FL118 and currently used therapeutics in different cancer models.
Our research was supported by RPCI start-up fund, RPCI Alliance Foundation, Elsa U Pardee Foundation and ACS-IRG.
Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Chi S-G, Kim H-J, Yang H, Pavletich NP, Carver BS, Erdjument-Bromage H, Tempst P, Cordon-cardo C, Misteli T, Jiang X, Pandolfi PP. Ubiquitination regulates nuclear PTEN import and tumor suppression as revealed by inherited mutation. Cell 2007: Vol 128, 141-156.
Wang X, Trotman L, Chen Z, Koppie T, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X. Nedd4-1 is the Proto-Oncogenic Ubiquitin Ligase for PTEN. Cell 2007: Vol 128, 129-139.
Wang X*, Wang J and Jiang J*: MdmX Protein Is Essential for Mdm2 Protein-mediated p53 Polyubiquitination. J. Biol.Chem. 2011: 286 (27), 23725-34, (*corresponding author)
Fan CD, Lum MA, Xu C, Black JD and Wang X*: Ubiquitin-dependent Regulation of Phospho-AKT Dynamics by the ubiquitin E3 ligase, NEDD4-1, in the IGF-1 Response. J. Biol. Chem. 2013: 288(3), 1674-84. (*corresponding author).
Xu C, Fan CD, and Wang X*: Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase. Oncogene 2014: 34(3):281-9.
Ling X, Xu C, Fan CD, Zhong K, Li F*and Wang X*: FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX. Cancer Research 2014: 74(24):7487-97. doi: 10.1158/0008-5472.CAN-14-0683. (*corresponding author).