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Zhimin (James) Lu, M.D., Ph.D.

Present Title & Affiliation

Primary Appointment

Professor, Department of Neuro-Oncology - Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Dual/Joint/Adjunct Appointment

Professor, Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Research Interests

Research Interests

·         Cancer metabolism

·         Tumorigenesis and tumor progression

 

Precise regulation of cellular signaling is important for cell growth and differentiation, cell metabolism, apoptosis, and organ and tissue development; dysregulation of cell signaling can lead to the development of cancer. In my laboratory, we study cancer metabolism, tumorigenesis, and tumor progression, focusing on the following research topics:

 

· Understanding how cancer advances by altering cell metabolism. Cancer cells have increased glucose uptake and elevated lactic acid production under aerobic conditions, which is termed the Warburg effect. Our research has revealed that pyruvate kinase M2 (PKM2), a glycolytic enzyme upregulated by NF-kB-dependent transcription (Molecular Cell, 2012; highlighted in Cancer Discovery and an MD Anderson news release), has an essential nuclear function in directly regulating β-catenin transactivation. These findings demonstrate that nuclear b‑catenin is transactivated via distinct mechanisms in response to growth factor or Wnt signaling. (Nature, 2011; Outstanding Research Publication Award at MD Anderson; highlighted in Cell’s “Leading Edge”, Nature SciBX, and Science Signaling). In addition, we discovered that PKM2 functioning as a protein kinase phosphorylates histone H3-T11, leading to H3-K9 acetylation, gene transcription, and cell cycle progression (Cell, 2012; highlighted in Science Signaling as a Signaling Breakthrough of the Year, Nature Reviews Cancer, and Cancer Discovery). This discovery demonstrates that a key glycolytic enzyme functions as a histone kinase and epigenetically regulates gene transcription in cancer cells. Furthermore, we have elucidated that nuclear PKM2 promotes the Warburg effect via a positive feedback mechanism by upregulating GLUT1, LDHA, and PKM2 expression (Nature Cell Biology, 2012; highlighted in Nature Chemical Biology and an MD Anderson news release). Our recent studies demonstrate that PKM2 regulates chromosome segregation and mitotic progression of tumor cells by phosphorylation of Bub3 (Molecular Cell, 2014; highlighted in Cancer Discovery and an MD Anderson news release). These studies systematically elucidate the mechanisms underlying a growth factor-promoted Warburg effect and the metabolic and non-metabolic functions of PKM2 in tumor development.

 

· Understanding how cancer cells migrate, invade, and metastasize by altering cell–cell contact and cell–extracellular matrix (ECM) interaction. We have found that EGFR activation promotes tumor cell invasion and metastasis by disrupting cell–cell contact, which is mediated by caveolae-dependent endocytosis of E-cadherin, Snail-regulated transcriptional repression of E-cadherin, and activation of signaling molecules in caveolae (Cancer Cell, 2003). In addition, EGFR activation initiates intracellular crosstalk between EGFR- and Wnt-induced signaling pathways and promotes b-catenin transactivation by releasing b-catenin from cell adhesion complexes. This regulation is accomplished by the disruption of the E-cadherin–b-catenin interaction mediated by AKT-dependent b-catenin phosphorylation and abrogation of the b-catenin and a-catenin interaction mediated by CK2-dependent a-catenin phosphorylation (Molecular Cell, 2009). Furthermore, the activation of EGFR or Ras reduces focal adhesion by dephosphorylating and inhibiting the focal adhesion kinase (FAK), which is mediated by ERK-dependent FAK phosphorylation at S910, PIN1-dependent prolyl isomerization of FAK, and subsequent recruitment of PTP-PEST phosphatase for FAK dephosphorylation at Y397 (Molecular Cell, 2009). The combination of disrupted cell–cell contact, reduced focal adhesion, and accelerated turnover of focal contacts promotes tumor cell migration, invasion, and metastasis.

 

· Understanding how cancer progresses by promoting cell survival. In our research on the regulation of cell survival and apoptosis, we have found that c-Jun, a major transcription factor in the activating protein 1 (AP-1) family, is downregulated in response to stress stimulation and chemotherapeutic drug treatment. The downregulation of c-Jun, which is regulated by MEKK1 (functioning as a MAP kinase kinase kinase and an E3 ligase)-mediated ubiquitination (Molecular Cell, 2002) and HDAC3-dependent transcriptional repression, promotes cell apoptosis (Molecular Cell, 2007). Differential regulation of c-Jun protein plays an instrumental role in the chemoresistance of cancer cells.

 

 

Office Address

The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd.
Department of Neuro-Oncology - Research
Unit Number: 1002
Houston, TX 77030
Room Number: BSRB S5.8116B
Email: zhiminlu@mdanderson.org

Education & Training

Degree-Granting Education

1998 The Graduate School and University Center, City University of New York, New York, NY, PHD, Molecular, Cellular and Developmental Biology
1986 Taishan Medical College, Shandong, China, MD, Medicine

Postgraduate Training

1/1999-9/2003 Research Fellowship, Department of Molecular and Cell Biology, Cancer Center Designated by the National Cancer Institute, The Salk Institute for Biological Studies, La Jolla, CA, Tony Hunter
9/1986-1/1992 Physician/Oncologist, Qingdao Hospital, Qingdao, China

Experience/Service

Other Appointments/Responsibilities

Research Associate/Postdoctoral Fellow, The Salk Institute for Biological Studies, La Jolla, CA, 1/1999-9/2003
Physician and Oncologist, Qingdao Hospital, Qingdao, NY, China, 9/1986-1/1992

Institutional Committee Activities

Member, The Multidisciplinary Research Advisory Committee (MRAC), 2012-present
Chair, The Odyssey Program Advisory Committee, 2011-present
Member, Brain Tumor Center (BTC) Research Seminar Series Committee, 2010-present
Member, The Cancer Biology Program International Student Admission Committee of Graduate School of Biomedical Sciences (GSBS), 2009-present
Member, Brain Tumor Center (BTC) Laboratory Sciences Committee, 2006-present

Honors and Awards

2013 The Potu N. Rao Award for Excellence in Basic Science, The University of Texas M.D.Anderson Cancer Center
2012 The James S. McDonnell Foundation Scholar Award, The James S. McDonnell Foundation
2011 The Faculty Scholar Award, The University of Texas MD Anderson Cancer Center
2009-2013 American Cancer Society Research Scholar, American Cancer Society
2008 Peter Steck Memorial Young Investigator Award, Pediatric Brain Tumor Foundation
2005 Wang Kuan-Cheng Foundation Award, Chinese Academy of Science
2000 California Breast Cancer Research Program Postdoctoral Fellowship, California Breast Cancer Research Program

Selected Publications

Peer-Reviewed Original Research Articles

1. Xia Y, Yang W, Bu W, Ji H, Zhao X, Zheng Y, Lin X, Li Y, Lu Z. Differential regulation of c-Jun plays an instrumental role in chemoresistance of cancer cells. J Biol Chem 288(27):19321-9, 2013. PMID: 23678002.
2. Zheng Y, Yang W, Aldape K, He J, Lu Z. EGF-enhanced vascular cell adhesion molecule-1 (VCAM-1) expression promotes macrophase and glioblastoma cell interaction and tumor cell invasion. J Biol Chem 288(44):31488-95, 2013. PMCID: PMC24045955.
3. Jiang Y, Li X, Yang W, Hawke D, Zheng Y, Xia Y, Aldape K, Wei C, Guo F, Chen Y, and Lu Z. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Molecular Cell, 2013. PMID: 24316223.
4. Yang W and Lu Z. Regulation and function of pyruvate kinase M2 in cancer. Cancer Lett. 2013. PMID: 23791887.
5. Ji H, Lu Z. The role of protein kinase CK2 in glioblastoma development. Clinical Cancer Research, 2013. PMID: 24166907.
6. Desai S, Ding M, Wang B, Lu z, Zhao Q, Shaw K, Yung WK, Weinstein JN, Tan M, Yao J. Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers. Oncotarget, 2013. PMID: 24077665.
7. Yang W, Xia Y, Hawke D, Li X, Liang J, Aldape K, Hunter T, Yung WK, and Lu Z. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150(4):685-696, 8/2012.
8. Ji H, Ding Z, Hawake D, Jiang B, Mills G, Lu Z. AKT-dependent Phosphorylation of Niban Regulates Nucleophosmin- and MDM2-Mediated p53 Stability and Cell Apoptosis. EMBO Reports 13(6):554-60, 6/2012. PMID: 22510990.
9. Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, You M, Koh M, Cote G, Aldape L. Li Y, Verma I, Chiao P, and Lu Z. EGFR-induced and PKC monoubiquitylation-dependent NF-kB activation upregulates PKM2 expression and promotes tumorigenesis. Molecular Cell 48(5):771-84, 2012. PMID: 23123196.
10. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Fang G, Lyssiotis C, Aldape K, Cantley L, and Lu Z. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nature Cell Biology 14(12):1295-304, 2012. PMID: 23178880.
11. Lu Z. Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis. Chin J Cancer 31(1):5-7, 2012.
12. Lu Z. PKM2 functions as a histone kinase. Cell Cycle 11(22):4101-2, 2012. PMID: 23070542.
13. He J, Xu Q, Jing Y, Agani F, Qian X, Carpenter R, Li Q, Wang X, Peiper S, Lu Z, Liu L, and Jiang B. Reactive oxygen species regulate ERBB2 and ERBB3 expression via miR-199a/125b and DNA methylation. EMBO Reports 13(12):1116-22, 2012. PMID: 23146892.
14. Yang W, Xia X, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 480(7375):118-22, (2011 Outstanding Research Publication Award at MDACC; Highlighted Cell Leading Edge, Nature SciBX, Science Signaling, Cancer Research, Cell Research, Chinese journal of Cancer, Future Oncology, & Faculty of 1000 Biology.), 12/2011. PMID: 22056988.
15. Liu DX, Qian D, Wang B, Yang JM, Lu Z. p300-Dependent ATF5 Acetylation Is Essential for Egr-1 Gene Activation and Cell Proliferation and Survival. Mol Cell Biol 31(18):3906-16, 9/2011. PMID: 21791614.
16. Chiu WT, Lee HT, Huang FJ, Aldape KD, Yao J, Steeg PS, Chou CY, Lu Z, Xie K, Huang S. Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition. Cancer Res 71(14):4932-43, 7/2011. PMID: 21622714.
17. Ji H, Wang J, Fang B, Fang X, Lu Z. a-catenin inhibits glioma cell migration, invasion, and proliferation by suppression of ß-catenin transactivation. J Neurooncol. 103(3):445-51, 2011. PMID: 20872274.
18. Guo W, Wu S, Wang L, Wein X, He Y, Liu X, Wang J, Lu Z, Hollingshead M, Fang B. Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition. PLoS One 6(12):e28487, 2011. PMID: 22174819.
19. Zheng Y, Yang W, Xia Y, Hawke D, Liu DX, Lu Z. Ras-induced and ERK1/2 Phosphorylation-Dependent Isomerization of PTP-PEST by PIN1 Promotes FAK Dephosphorylation by PTP-PEST. Mol Cell Biol 31(21):4258-69, 2011. PMID: 21876001.
20. Ding Z, Liang J, Li J, Lu Y, Ariyaratna V, Lu Z, Davies MA, Westwick JK, Mills GB. Physical association of PDK1 with AKT1 is sufficient for pathway activation independent of membrane localization and phosphatidylinositol 3 kinase. PLoS One 5(3):e9910, 2010. PMCID: PMC2845649.
21. Lu Z, and Hunter T. Ubiquitination and proteasomal degradation of p27kip1, p21cip1, and p57kip2. Cell Cycle 12:2342-2352, 2010.
22. Ji H, Wang J, Nika H, Hawke D, Keezer S, Ge Q, Fang B, Fang X, Fang D, Litchfield DW, Aldape K, Lu Z. EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin. Mol Cell 36(4):547-59 (Selected as the feature article by Mol Cell and highlighted in Cell and M.D. Anderson News Release), 11/2009. PMCID: PMC2784926.
23. Zheng Y, Lu Z. Paradoxical roles of FAK in tumor cell migration and metastasis. Cell Cycle 8(21):3474-9, 11/2009. PMID: 19829089.
24. Chen H, Xia Y, Fang D, Hawke D, Lu Z. Caspase-10-mediated heat shock protein 90 beta cleavage promotes UVB irradiation-induced cell apoptosis. Mol Cell Biol 29(13):3657-64, 7/2009. PMCID: PMC2698753.
25. Lu Z, Hunter T. Degradation of activated protein kinases by ubiquitination. Ann Rev Biochem 78:435-75, 7/2009. PMCID: PMC2776765.
26. Zheng Y, Xia Y, Hawke D, Halle M, Tremblay M, Gao X, Zhou X, Aldape K, Cobb M, Xie K, He J, and Lu Z. FAK phosphorylation by ERK primes Ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Mol Cell 35(1):11-25 (Highlighted in Mol Cell and Faculty of 1000 Biology), 7/2009. PMCID: PMC2715139.
27. Liu S, Fang X, Hall H, Yu S, Smith D, Lu Z, Fang D, Liu J, Stephens C, Woodgett J, and Mills G. Homozygous deletion of glycogen synthase kinase 3 beta bypasses senescence allowing Ras transformation of primary murine fibroblasts. Proc Natl Acad Sci USA 105(13):5248-53, 4/2008. PMCID: PMC2278194.
28. Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282(15):11221-229, 4/2007. PMCID: PMC1850976.
29. Xia Y, Wang J, Liu TJ, Yung WK, Hunter T, Lu Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. (Selected as the feature article by Mol Cell and received MDACC Nycomed GmbH Outstanding Research Publication Award in 2007). Mol Cell 25(2):219-32, 1/2007. PMCID: PMC1829326.
30. Xia Y, Wang J, Xu S, Johnson GL, Hunter T, Lu Z. MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress. Mol Cell Biol 27(2):510-517, 1/2007. PMID: 17101801.
31. Lu Z, Xu S. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life 58(11):621-31, 11/2006. PMID: 17085381.
32. Ya X, Lu Z. The ubiquitination-mediated degradation of epidermal growth factor receptor. (Review) . Acta Acad Med Sin 27(1):120-27, 2/2005. PMID: 15782507.
33. Lu Z, Hunter T. Wnt-independent beta-catenin transactivation in tumor development. Cell Cycle 3(5):571-3, 5/2004. PMID: 15107603.
34. Lu Z, Ghosh S, Wang Z, Hunter T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4(6):499-515 (Highlighted in: Nat Rev Cancer 2004; 4:90-91; Nature Signaling & Update/The signaling gateway 2004, and Faculty of 1000 Biology), 12/2003. PMID: 14706341 (Highlighted in: Nat Rev Cancer 2004; 4:90-91; Nature Signaling & Update/The signaling gateway 2004, and Faculty of 1000 Biology).
35. Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol Cell 9(5):945-56, (Highlighted in: Nat Rev Mol Cell Biol 2002;3:473; Nature-Signaling Update/the signaling gateway, 2002; and Faculty of 1000 Biology), 5/2002. PMID: 12049732.
36. Lu Z, Jiang G, Blume-Jensen P, Hunter T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 21(12):4016-31, 6/2001. PMID: 11359909.
37. Zhong M*, Lu Z*, Abbas T, Hornia A, Chatakondu K, Barile N, Kaplan P, Foster DA (*equal contribution). Novel tumor-promoting property of tamoxifen. Cell Growth Differ 12(4):187-92, 4/2001. PMID: 11331247.
38. Goi T, Shipitsin M, Lu Z, Foster DA, Klinz SG, Feig LA. An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. EMBO J 19(4):623-30, 2/2000. PMID: 10675331.
39. Lu Z, Hornia A, Joseph T, Sukezane T, Frankel P, Zhong M, Bychenok S, Xu L, Feig LA, Foster DA. Phospholipase D and RalA cooperate with the epidermal growth factor receptor to transform 3Y1 rat fibroblasts. Mol Cell Biol 20(2):462-7, 2000. PMID: 10611224.
40. Hornia A*, Lu Z*, Sukezane T, Zhong M, Joseph T, Frankel P, Foster DA (*equal contribution). Antagonistic effects of protein kinase C alpha and delta on both transformation and phospholipase D activity mediated by the epidermal growth factor receptor. Mol Cell Biol 19:7672-80, 11/1999.
41. Lu Z, Liu D, Hornia A, Devonish W, Pagano M, Foster DA. Activation of protein kinase C triggers its ubiquitination and degradation. Mol Cell Biol 18(2):839-45, 2/1998. PMID: 9447980.
42. Lu Z, Hornia A, Jiang YW, Zang Q, Ohno S, Foster DA. Tumor promotion by depleting cells of protein kinase C delta. Mol Cell Biol 17(6):3418-28, 6/1997. PMID: 9154841.
43. Jiang H, Luo JQ, Urano T, Frankel P, Lu Z, Foster DA, Feig LA. Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature 378(6555):409-12, 11/1995. PMID: 7477381.

Book Chapters

1. Lu Z, Hunter T. MEKK1: Dual function as a protein kinase and a ubiquitin protein ligase. In: Protein Degradation: The Ubiquitin-Proteasome System. 2. Ed(s) RJ Mayer, A Ciechanover, M Rechsteiner. WILEY-VCH Verlag GmbH & Co. KGaA: Germany, 79-89, 2006. ISBN: 3-527-31130-0.
2. Lu Z. Activation of Wnt Signaling in Tumor Development. In: Current Topics in Human Genetics: Studies in Complex Diseases. Ed(s) HW Deng, H Shen, YL Liu, H Hu. World Scientific Publishing Co: Singapore, 809-32, 2007. ISBN: 981-270-472-8.

Last updated: 2/12/2014