Faculty » Research Information

Hua Lu, PhD

Hua Lu, MB (US MD equivalent), PhD

Professor and Chair
Reynolds and Ryan Families Chair in Translational Cancer
Tulane University School of Medicine
Department of Biochemistry and Molecular Biology
1430 Tulane Avenue, #8643
New Orleans, LA 70112
(504) 988-5293

» Lu Lab Website

Research Interests/Area of Study: Molecular dissection and translational research of the p53 and c-myc networks in controlling cell growth, senescence, death, differentiation, and tumorigenesis.

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 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. 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:

1. To understand the biochemical mechanism underlying the regulation of MDM2 by ribosomal proteins, leading p53 activation, and the role of these ribosomal proteins in cell cycle regulation and tumorigenesis;

2. To elucidate molecular mechanisms for the 14-3-3 regulation of MDMX, leading p53 activation, in response to metabolic, hypoxia and DNA damage signals, and also the role of 14-3-3 in tumorigenesis;

3. To illustrate the role of ribosomal proteins in regulating c-Myc activity and tumorigenesis;

4. To determine the role of newly identified miRNAs in the p53 and c-Myc pathways;

5. 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, gene microarray, molecular and cellular biological methods as well as genetic methods (such as murine 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. 

 The Ribosomal Stress-p53/c-Myc Pathway

(Above image) The Ribosomal Stress-p53/c-Myc Pathway.

Representative and Recent Publications:

Zeng, X.Y., Chen, L., Jost, C.A., Maya, R., Kaelin, W.G., Oren, M., Chen, J., and Lu, H. (1999) MDM2 suppresses p73 function without promoting p73 degradation. Mol. Cell. Biol. 19, 3257-3266.

Zeng, X.Y., Li, X., Miller, A., Yuan, Z., Yuan, W., Kwok, R.P., Goodman, R., and Lu, H. (2000) The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis. Mol Cell Biol. 20, 1299-310.

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.

Zeng, S.X., Dai, M.S., Keller, D., and Lu, H. (2002) SSRP1 functions as a co-activator of the transcriptional activator p63. EMBO J. 21, 5487-5497.

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.

Dai, M.D., Shi, D., Jin, Y., Sun, X.X., Zhang, Y., Grossman, S.R., and Lu H. (2006) Regulation of the MDM2-p53 Pathway by Ribosomal Protein L11 Involves a Post-ubiquitination Mechanism. J Biol Chem. 281, 24304-13. 

Landais, I., Lee, H.J., and Lu, H. (2006) Coupling caspase cleavage and ubiquitin-proteasome dependent degradation of SSRP1 during apoptosis. Cell Death & Differentiation. 13, 1866-78.

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.

Li, Y.P., Zeng, S.X., Landais, I., and Lu, H. (2007) Human SSRP1 has Spt16-dependent and independent roles in gene transcription. J. Biol. Chem. 282, 6936-6945.

Sun, X.X., Dai, M.S., and Lu, H. (2007) 5-Fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction. J. Biol. Chem. 282, 8052-8059.

Dai, M.S., Arnold, H., Sun, X.X., Sears, R., and Lu, H. (2007) Inhibition of c-Myc activity by ribosomal protein L11. EMBO J. 26, 3332-45.

Gallegos, J., Litersky, J., Lee, H.J., Sun, Y., Nakayama, K., Nakayama, K., and Lu, H. (2008) bTrCP activates and ubiquitylates TAp63g. JBC. 283, 66-75. 

Jin, Y.T., Zeng, S.X., Sun, X.X., Lee, H., Blattner, C., Xiao, Z.X., and Lu, H. (2008) MDMX promote proteasomal turnover of p21 during cell cycle independently of, but in cooperation with, MDM2. Mol Cell. Biol. 28, 1218-29.

Dai, M.S., Sun, X.X., and Lu, H. (2008) Abnormal expression of Nucleostemin activates p53 activity and induces cell cycle arrest via inhibition of MDM2. Mol. Cell. Biol. 28, 4365-76.

MacPatlin, M.M., Zeng, S.X., and Lu, H. (2008) Posphorylation and stabilization of TAp63g by IkB kinase-b. JBC. 283, 15754-61.

Zhang, Y. and Lu, H. (2009) Signaling to p53: Ribosomal proteins find their way. Cancer Cell (review). 16, 369-77.

Zeng, S.X., Li, Y.P., Jin, Y.T., Zhang, Q., Keller, D.M., McQuaw, C.M., Barklis, E., Stone, S., Hoatlin, M., Zhao, Y.M., and Lu, H. (2010) SSRP1 facilitates microtubule growth and bundling required for mitosis. Mol Cell. Biol. 30, 935-47.

Dai, M.S., Sun, X.X., and Lu, H. (2010) Ribosomal protein L11 associates with c-Myc at 5S rRNA and tRNA genes and regulates their expression. J Biol Chem. 285, 12587-94.

Lee, J.H., Zhang, Q., Jo, S., Chai, S.C., Oh, M., Im, W., Lu, H.*, and Lim, H.S*. (2011) “Novel pyrrolopyrimidine-based α-helix mimetics: cell permeable inhibitors of protein-protein interactions.” J. Am. Chem. Soc. 133, 676-9. (*co-corresponding authors).

Lee, JH. and Lu, H. (2011) 14-3-3{gamma} inhibition of MDMX-mediated p21 turnover independent of p53. J Biol Chem. 286, 5136-42.

Zhang, Y., Liao, J.M., Zeng, S.X., and Lu, H. (2011) p53 downregulates Down syndrome associated DYRK1A through miR-1246. EMBO Reports. 12, 811-7.

Lu, H. (2011) A ribosomal tactic to halt cancer. Nature Medicine (news & views). 17, 930-1.

Liao JM and Lu H. (2011) Auto-regulatory suppression of c-Myc by miR-185-3p. JBC. 286, 33901-9. 

Zhang, Q., Xiao, H., Chai, S.C., Hoang, Q.Q., and Lu, H. (2011) Hydrophilic residues are crucial for RPL11 interaction with the Zinc finger domain of MDM2 and p53 activation. JBC. 286, 38264-74.

Zhou, X., Hao, Q., Liao, J.M., Zhang, Q., and Lu, H. (2012) Ribosomal protein S14 regulates the MDM2-p53 loop upon ribosomal stress. Oncogene, in press.

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.

Lo, D., Dai, M.S., Sun, X., Zeng, S.X., and Lu, H. (2012) Ubiquitin- and MDM2-independent proteasomal turnover of nucleostemin in response to GTP depletion. JBC 287,10013-20.

Lee, J.H., Jin, Y.T., He, G.F., Zeng, S.X., Wang, V., Wah,l G.M., and Lu, H. (2012) Hypoxia activates tumor suppressor p53 by inducing ATR-Chk1 kinase cascade-mediated phosphorylation and 14-3-3gamma inactivation of MDMX. JBC 287, 20898-903. 

Zhang, Y.W., Zhang, Q., Zeng, S.X., Mayo, L., and Lu, H. (2012) Inauhzin and Nutlin3 Synergistically Activate p53 and Suppress Tumor Growth. Cancer Biology & Therapy 13, 915-24.

Dai, M.S., Challagundla, K.B., Sun, X.X., Palam, L.R., Zeng, S.X., Wek, R.C., and Lu, H. (2012) Physical and functional interaction between ARF and ribosomal protein L11 in regulating the p53-MDM2 feedback loop. JBC 287, 17120-9.

Liao, J.M. and Lu, H. (2012) Chromatin-immunoprecipitation of p53 responsive promoters. Methodology Mol Biol., in press.

Zhang, Q. and Lu, H. (2012) Identification of small molecules affecting p53-MDM2/MDMX interaction by fluorescence polarization. Methodology Mol Biol. In press.

Liao, J.M., Zhou, .X, Zhang, Y., and Lu, H. (2012) miR-1246: A new link of the p53 family with cancer and Down syndrome. Cell Cycle 11, 2643-30.

Zhou, X., Liao, J.M., Jiao, W.J., and Lu, H. (2012) Fission of the MDM2-p53 loop by ribosomal proteins. Genes & Cancer (invited review). In press.

1430 Tulane Ave, New Orleans, LA 70112