MB (U.S. MD equivalent): Jiangxi Medical College, China
PhD: Rutgers University/UMDNJ
Professor Lu received a Medical Bachelor degree (US MD equivalent) from Jiangxi Medical College, China in 1983, a Master of Science degree from Peking Union Medical College in Beijing in 1986, and a PhD degree from Rutgers University/Robert Wood Johnson Medical School in 1993. After completing his postdoctoral research at Princeton University, he was appointed as a tenure-track assistant professor at Oregon Health & Science University (OHSU) in 1997 and was promoted to a tenured associate professor there in 2003. He joined Indiana University School of Medicine as a full professor of Biochemistry and Molecular Biology/Daniel and Lori Efryomson Chair Professor of Oncology in 2007 before joining Tulane University School of Medicine in January 2012.
Professor Lu has expertise in the fields of protein chemistry, molecular biology, cancer mechanisms involving p53, the most important tumor suppressor, and c-Myc, one of the important oncoproteins, and translational and pharmacological cancer research. His research has led to the identification of several important protein regulators of p53 and its homologs as well as c-Myc and provides insight into the molecular mechanisms underlying cancer formation. One of his major contributions has been to uncover the previously under-appreciated ribosomal stress-p53 signaling pathway together with two other scientists. Part of his work will be useful for anti-cancer drug development. Recently his lab has identified a novel small molecule called Inauhzin that can suppress tumor growth by activating the p53 pathway as a potential anti-cancer drug candidate. Also, his lab has recently uncovered several novel p53 targets that play crucial roles in tumor development, progression and drug resistance and unveiled a unique mechanism underlying the gain of function (GOF) of a p53 hot spot mutation that is highly related to hepatitis-B virus (HBV)- and Aflatoxin B1- associated hepatocellular carcinoma (HCC). His own and collaborative work has resulted in approximately 130 high-quality publications in scientific journals, such as Nature, Science, Cell, Molecular Cell, Cancer Cell, Nature Communication, EMBO J, PNAS, EMBO Reports, EMBO Molecular Medicine, eLIFE, MCB, JBC, Cancer Research, Cell Death and Differentiation, Oncogene, Developmental Biology, Scientific Reports, and others.
Professor Lu serves as an Associate Editor for Journal of Molecular Cell Biology (JMCB), a Topic Editor for Frontier in Endocrinology and Oncology, and an editorial board member for Cancer Biology and Therapy. He has also served as an editorial board member for the International Journal of Cancer Research (US), the Journal of Biological Chemistry and the International Journal of Biochemistry and Molecular Biology. He has served as a standing member of the Tumor Progression and Metastasis (previous Pathology B) study section at the National Institutes of Health (NIH) and an ad hoc reviewer for a number of NIH study sections, a P01 review panel, and an NCI program review panel. He now serves as a standing member of the Drug Discovery and Molecular Pharmacology (DMP) study section at NIH and as a scientific advisory board member for the Diamond Blackfan Anemia (DBA) Foundation, Inc. in New York. He has received the Schering Corp Fellowship for Outstanding Performance in Biochemistry and Molecular Biology, a postdoctoral fellowship by the Damon Runyon-Walter Winchell Cancer Research Fund, the New Jersey Cancer Research Award for Scientific Excellence, and the Teaching Excellence award at OHSU. He has been invited more than 200 times to give seminars and lectures at various national and international conferences as well as research institutions and biotech or pharmaceutical companies.
Research Interests/Area of Study: Cancer Biology, Metabolism, Mechanisms and Therapeutics Discovery Involving p53 and c-Myc Pathways.
Summary: The Lu laboratory is interested in understanding the molecular and biochemical basis that underlies physiological and pathological signaling pathways (growth, metabolic, hypoxia, or DNA damage signals), which lead to gene expression and subsequent cell growth arrest, differentiation, senescence, autophagy, or apoptosis.
The abnormal alterations of these pathways often result in and/or facilitate tumorigenesis. A remarkable example of the tumorigenic abnormality is the alternation of the components in the stress signaling pathway that is mediated by the p53 tumor suppressor protein and its negative regulators, such as MDM2 and MDMX. Genetic studies show that MDM2 and MDMX are the physiological feedback regulators of p53, and these proteins play important roles in tumorigenesis. MDM2 and MDMX repress p53 function by mediating its degradation and directly suppressing its activity. Decetylation of p53 mediated by SIRT1 or HDAC1 can facilitate MDM2/MDMX-mediated p53 suppression. Various stress signals lead to p53 activation by blocking this feedback regulation. Recently, my laboratory has identified a novel class of small molecules, named Inauhzin that can inhibit SIRT1 and IMPDH2 activity, activate p53 and induce p53-dependent apoptosis and senescence, consequently suppressing tumor growth. Another example of the cancerous abnormality is the overexpression of oncogenes, such as c-myc or mutated p53s. Our recent studies show that ribosomal proteins regulate c-Myc activity. Also, a newly identified miRNA can regulate c-Myc expression and activity in an auto-regulatory fashion. To understand the molecular and biochemical mechanisms for cell proliferation and tumorigenesis involving the p53 and c-Myc pathways, my laboratory focuses on the following projects:
- To understand the biochemical mechanism underlying the regulation of MDM2 by ribosomal proteins, leading p53 activation, and the role of these ribosomal proteins and their regulators, such as RBM10 or Spin1, in cell cycle regulation and tumorigenesis;
- To elucidate molecular mechanisms for the AMPK regulation of MDMX, leading p53 activation, in response to metabolic and hypoxia signals by using genetically manipulated mouse models, such as a double knockin (DKI) mouse line that harbors both MDM2 and MDMX point mutation, impairing the ribosomal stress-MDM2- and metabolic stress-AMPK-MDMX-p53 pathways;
- To illustrate the roles of several newly identified p53 targets, such as PHLDB2, NGFR, or GRIN2C, in controlling p53-dependent and p53-independent functions during tumorigenesis and drug resistance;
- To determine the roles of p53 hot spot mutations in tumor development, progression and drug resistance, such as p53 R249S in HCC, or R273H and R248W in lung and colon cancer metabolism, development and drug resistance, particularly revealing the molecular insights into the roles of their GOFs in cancer stem cell proliferations and cancer development as well as cancer immunology;
- To determine the role of CCDC3, a newly identified p63 target, in lipid metabolism, fatty liver development, and inflammatory response as well as the association of these physiological and pathological events with cancer development and progression;
- To understand the role of unique posttranslational modifications of p53 or c-Myc in regulation of these transcriptional factors’ functions and cancer biology;
- To ultimately develop anti-cancer drugs by targeting the p53 (such as Inauhzin) and c-Myc pathways.
Diverse approaches including quantitative and analytical protein biochemistry, chemical biology, proteomics, immunological tools, gene microarray, RNA seq, molecular and cellular biological methods as well as genetic methods (such as murine model, orthotopic and PDX tumor model systems) will be employed in these studies. We will also pursue translational research by screening anti-cancer drugs targeting the above pathways and examining molecular alternations of these pathways in human cancers. The effort will be complemented by collaborating with other groups on and off the campus.
Representative and Recent Publications:
Kobet, E., Zeng, X., Zhu, Y., Keller, D., and Lu, H. (2000) MDM2 Inhibits p300-mediated p53 Acetylation and Activation by Forming a Ternary Complex with Two Proteins. Proc. Natl. Acad. Sci. USA. 97,12547-12552 4.
Keller, D., Zeng, X.Y., Wang, Y., Zhang, Q., Kapoor, M., Zhao, Y.M., Goodman, R., Lozano, G., and Lu, H. (2001) A DNA damage responsive p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol. Cell. 7, 283.
Jin, Y.T., Lee, H.J., Zeng, S.X., Dai, M.S., and Lu, H. (2003) MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J. 22, 6365-6377.
Dai, M.S. and Lu, H. (2004) Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem. 279, 44475-82.
Dai, M.S., Zeng, S.X., Jin, Y.T., Sun, X.X., David, L., and Lu, H. (2004) Ribosomal protein L23 activates p53 by abrogating MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol. Cell. Biol. 24, 7654-7668.
Jin, Y., Dai, M.S., Lu, S.Z., Xu, Y., Luo, Z., Zhao, Y., and Lu, H. (2006) 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J. 25, 1207-18.
Dai, M.S., Grant, H., Sun, X.X., Sears, R., and Lu, H. (2007) Inhibition of c-Myc activity byribosomal protein L11. EMBO J. 26, 3332-45.
Zhang, Q., Zeng, S.X., Zhang, Y., Zhang, Y.W., Ding, D.R., Ye, Q.Z., Meroueh, S., and Lu, H. (2012) A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumor growth through activation p53. EMBO Mol Med. 4, 298-312.
Zhang, Q., Zhou, X., Wu, R.Z., Mosley, A., Zeng, S.X., Xing, Z., and Lu, H. (2014) The role of IMPDH2 in Inauhzin induced ribosomal stress. eLIFE. Oct 27; 3. doi: 10.7554/eLife.03077.
Zhou, X., Hao, Q., Zhang, Q., Liao, J.M., Ke, J.W., Liao, P., Cao, B., and Lu, H. (2015) Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition. Cell Death & Differentiation. 22, 755-66.
He, G.F., Zhang, Y.W., Lee, J.H., Zeng, S.X., Wang, V., Luo, Z.J., Dong, X.C., Viollet, B., Wahl, G.M., and Lu, H. (2014) AMP-activated kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol Cell Biol. 34, 148-87.
Cao, B., Wang, K.B., He, M.F., Liao, J.M., Zhou, X., Liao, P., Zeng, S.X., Chen, L.Z., He, Y.L., Li, W., and Lu H. (2016) p53 inactivates oncogenic cAMP-specific phosphodiesterase 4D via miR-139-5p. eLIFE. pii: e15978. doi: 10.7554/eLife.15978.
Chao, T.F., Zhou, X., Liu, H.B., Cao, B., Zeng, S.X., Liao, P., Chen, Y., Park, H.W., and Lu, H. (2016) Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53. Nature Communications. 7:13755. doi: 10.1038/ncomms13755.
Zhou, X., Hao, Q., Liao, P., Luo, S., Zhang, M., Hu, G., Liu, H.B., Zhang, Y.W., Cao, B., Baddoo, M., Flemington, E., Zeng, S.X., and Lu, H. (2016) Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator. eLIFE. pii:e15099. doi: 10.7554/eLife.15099.
Zhang, Y.W., Zeng, Y.X., Hao, Q., and Lu, H. (2017) Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner. Developmental Biology. 12-1606(16), 30854-5.
Liao, W,J., Liu, H.B., Zhang, Y.W., Jung, J., Su, X., Chen, T.J., Kim, Y.C., Wang, S.M., Czarny-Ratajczak, M., Flores, E., Zeng, S.X.*, and Lu, H*. (2017) CCD3: A new p63 target involved in regulation of lipid metabolism. Scientific Reports (Nature press). 7:9020 (doi: 10.1038/s41598-017-09228-8; * co-corresponding authors).
Liao, P., Zeng, S.X., Zhou, X., Zhou, F., Chen, T., Cao, B., Jung, J.H., Sal Del, G., Luo, S., and Lu, H. (2017) Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding. Mol Cell. 2017 Dec 21;68(6):1134-1146.
Cao B, Fang Z, Liao P, Zhou X, Xiong J, Zeng S, Lu H. (2017) Cancer-mutated ribosome protein L22 (RPL22/eL22) suppresses cancer cell survival by blocking p53-MDM2 circuit. Oncotarget. 2017 Oct 6;8(53):90651-90661. doi: 10.18632/oncotarget.21544. eCollection 2017 Oct 31.
Fang ZL, Cao B, Liao JM, Deng J, Plummer KD, Liao P, Liu T, Zhang W, Zhang K, Li L, Margolin D, Zeng SX, Xiong JP, and Lu H. (2018) SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer. Elife 2018, 7.
Dr. Lu’s publications can be viewed on the PubMed website.