Lu Yang, Ph.D.
Department: Department of Pharmacology and Toxicology
Phone: (804) 628-8889
Massey Cancer Center
401 College Street Goodwin Research Laboratories, Room 281,
Richmond, VA 23298
B.Sc. in Biotechnology (2005) Zhejiang Chinese Medical University, China
Ph.D. in Biochemistry and Molecular Biology (2010), Zhejiang University, China
Therapeutic targets and drug development
Our laboratory focuses on the novel functions of peptidase D (PEPD). We have found that PEPD is both a novel ligand of EGFR and the long-sought elusive HER2 ligand. Most importantly, we have shown that PEPD is actually an inhibitory ligand of EGFR and HER2 and hence PEPD inhibits EGFR- and/or HER2-overexpressing cells and tumors both in vitro and in vivo.
Furthermore, we found that intracellular PEPD binds to and regulates p53 and mutant p53. We showed that PEPD binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. Our results indicate that the PEPD-p53 complex is critical for p53 response to stress. Moreover, PEPD also binds to and regulates mutant p53. Our results indicate that disrupting their binding in cells by PEPD knockdown reactivates each p53 mutant, unleashing both transcription-dependent and -independent tumor suppressing activities. This discovery advances our understanding of the function and regulation of p53 mutants and breaks new ground for developing novel cancer treatment strategies.
- Yang L, Bhattacharya A, Li Y, Sexton S, Ling X, Li F, Zhang Y. Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer. Journal of Experimental & Clinical Cancer Research, 41, 184, 2022.
- Yang L, Li Y, Bhattacharya A, Zhang Y. Loss of peptidase D binding restores the tumor suppressor functions of oncogenic p53 mutants. Communications Biology, 4, 1373, 2021.
- Yang L, Li Y, Bhattacharya A, Zhang Y. A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer. Science Translational Medicine, 11, eaav1620, 2019.
- Yang L, Li Y, Bhattacharya A, Zhang Y. PEPD is a pivotal regulator of p53 tumor suppressor. Nature Communications, 8, 2052, 2017.
- Liu X, Campanac E, Cheung HH, Ziats MN, Canterel-Thouennon L, Raygada M, Baxendale V, Pang AL, Yang L, Swedo S, Thurm A, Lee TL, Fung KP, Chan WY, Hoffman DA, Rennert OM. Idiopathic autism: cellular and molecular phenotypes in pluripotent stem cell-derived neurons. Molecular Neurobiology, 54, 4507-4523, 2017.
- Yang L, Li Y, Bhattacharya A, Zhang Y. Inhibition of ERBB2-overexpressing tumors by recombinant human prolidase and its enzymatically inactive mutant. EBioMedicine, 2,396- 405, 2015.
- Yang L, Li Y, Zhang Y. Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth. Cell Death & Disease, 5, e1211, 2014.
- Yang L, Li Y, Ding Y, Choi KS, Kazim AL, Zhang Y. Prolidase directly binds and activates epidermal growth factor receptor and stimulates downstream signaling. Journal of Biological Chemistry, 288, 2365-2375, 2013.
- Geng F, Tang L, Li Y, Yang L, Choi KS, Kazim AL, Zhang Y. Allyl isothiocyanate arrests cancer cells in mitosis, and mitotic arrest in turn leads to apoptosis via Bcl-2 phosphorylation. Journal of Biological Chemistry, 286, 32259-32267, 2011.
- Luo K, Sun, J, Chan J, Yang L, Wu S, Fung K, Liu F. Anticancer effects of imperatorin isolated from Angelica dahurica: induction of apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways. Chemotherapy, 57,449-459, 2011.
- Yang L, Liu X, Lu Z, Chan J, Zhou L, Fung KP., Wu P, Wu S. Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. Cancer Letters, 298,128-138, 2010.
- Yang L, Wu D, Luo K, Wu S, Wu P. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells. Cancer Letters, 276,180-188, 2009.
- Ren G, Zhao Y, Yang L, Fu C. Anti-proliferative effect of clitocine from the mushroom Leucopaxillus giganteus on human cervical cancer HeLa cells by inducing apoptosis. Cancer Letters, 262,190-200, 2008.
- Wang T, Jiang X, Yang L, Wu S. pH-gradient counter-current chromatography isolation of natural antioxidant chlorogenic acid from Lonicera japonica Thumb. using an upright coil planet centrifuge with three multi-layer coils connected in series. Journal of Chromatography A, 1180, 53-58, 2008.
- Wu S, Yang L, Gao Y, Liu X, Liu F. Multi-channel counter-current chromatography for high-throughput fractionation of natural products for drug discovery. Journal of Chromatography A,1180, 99-107, 2008.
- Yang L, Wu S, Zhang Q, Liu F, Wu P. 23,24-Dihydrocucurbitacin B induces G(2)/M cell-cycle arrest and mitochondria-dependent apoptosis in human breast cancer cells (Bcap37). Cancer Letters, 256, 267-278, 2007.
- Liu F, Wu S, Chen Y, Yang L, Wu P. Verticillin chloroform solvate. Acta Crystallographica Section E-Structure Reports Online. 62, 974-976, 2006.