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

1986, Taishan Medical School
1998, City University of New York

UT M. D. Anderson Cancer Center
Neuro-Oncology and Genetics

Research Interests: Signal transduction, oncogenesis, tumor cell invasion and metastasis, and ubiquitination

Precise regulation of cellular signaling is important for cell growth and differentiation, apoptosis, and organ and tissue development; its dysregulation may lead to cancer. Cancer develops as a result of alterations of normal intracellular and intercellular signaling. As key elements in cancer development, protein kinases play important roles in transducing, amplifying, and integrating cellular signals. In my laboratory, we study tumorigenesis and tumor progression, focusing on the following research topics:

1) Understanding how activations of growth factor receptor kinases, such as epidermal growth factor receptor (EGFR), promote tumorgenesis and tumor cell invasion and metastasis by regulating E-cadherin-mediated cell-cell adhesion and focal adhesion kinase (FAK)-involved cell-extracellular matrix (ECM) interactions.

2) Understanding the intracellular crosstalk between activation of growth factor receptor kinases- and Wnt-induced signaling pathways and intercellular crosstalk between tumor cells and neighboring cells.

3) Understanding the regulation of oncogenic transcriptional factors, such as Jun and Fos, in tumorgenesis and cancer treatment.

We have found that various human cancers that overexpress EGFR initiate migration and invasion by disrupting cell-cell contacts and cell-ECM interactions. These changes result from downregulation of E-cadherin, increased beta-catenin transctivation, and dephosphorylation of FAK. The consequential alteration in gene expression induced by the functional regulation of signaling molecules such as caveolin-1, beta-catenin, and c-Jun provides additional drive for tumor cell invasion and metastasis. To understand the regulation of cell survival and apoptosis in tumor development and treatment, 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 regulated by HDAC3-dependent transcriptional repression and MEKK1 (functioning as a MAP kinase kinase kinase and an E3 ligase)-mediated ubiquitination promotes cell apoptosis. Gaining further understanding of tumorigenesis by mechanistic studies of intracellular signaling, communication between tumor cells and surrounding normal cells, and communication between tumor cells and ECM will hopefully provide us with more approaches to cancer treatment.
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Jiang H., Luo JQ, Urano T, Frankel P, Lu Z, Foster DA, Feig LA. (1995) Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature; 378:409-412.

Lu Z, Hornia A, Jiang YW, Sang Q, Onho S, Foster DA (1997) Tumor promotion by depleting cells of Protein Kinase C d. Mol Cell Biol 1997;17:3418-3428.

Lu Z, Liu D, Hornia W, Devonish W, Pagano M, Foster DA (1998) The activation of Protein Kinase C triggers its ubiquitnation and downregulation. Mol Cell. Biol. 18:839-845. Highlighted in ASM News 1998;64(4):218.

Hornia A*, Lu Z*, Sukezane T, Zhong M, Joseph T, Frankel P, Foster DA (1999) Antagonistic effects of protein kinase C a and d on both transformation and phospholipase D activity mediated by the epidermal growth factor receptor. Mol Cell Biol;19:7672-7680.* Equal contribution

Lu Z, Hornia A, Joseph T, Sukezane T, Frankel P, Zhong M, Bychenok S, Xu L, Feig LA, Foster DA (2000) Phospholipase D and RalA cooperate with the epidermal growth factor receptor to transform 3Y1 rat fibroblasts. Mol Cell Biol; 20:462-467.

Goi T, Shipistin M, Lu Z, Foster DA, Feig LA (2000) An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. EMBO J; 19: 623-630.

Lu Z, Jiang G, Bume-Jensen P, Hunter T (2001) 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.

Zhong M*, Lu Z*, Hornia A, Abbas T, Chatakondu K, Barile N, Kaplan P, Foster DA (2001) Novel tumor-promoting property of tamoxifen. Cell Growth Differ; 12:187-92. * Equal contribution

Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T (2002) The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Molecular Cell; 9:945-956. Highlighted in Nature Reviews Molecular Cell Biology 3(7):473, 2002, Nature-Signaling Update/the signaling gateway, 2002, (UBIQUITYLATION, Dual control), and EMBO Reports 2002;3:1023-1028.

Lu Z*, Ghosh S, Wang Z, Hunter T* (2003) Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of b-catenin, and enhanced tumor cell invasion. Cancer Cell; 4:499-515. Highlighted in Nature Reviews Cancer 2004;4:90-1 and Nature-Signaling & Update/the Signaling gateway 2004, (CAVI connection). * Corresponding author

Lu Z, Hunter T (2004) Wnt-independent b -catenin transactivation in tumor development. Cell Cycle; 3:571-573.

Lu Z, Xu S (2006) ERK1/2 MAP kinases in cell survival and apoptosis (Review). IUBMB Life (International Union of Biochemistry and Molecular Biology: Life), 58(11): 621- 631.

Xia Y, Wang J, Xu S , Johnson G, Hunter T, Lu Z (2007) MEKK1 Mediates Ubiquitination and Degradation of c-Jun in Response to Osmotic Stress. Mol Cell Biol; 27(2):510-517.

Xia Y, Wang J, Xu S, Liu TJ, Johnson G, Yung WK, Hunter T, Lu Z (2007) c-Jun Downregulation by HDAC3-Dependent Transcriptional Repression Promotes Osmotic Stress-induced Cell Apoptosis. Molecular Cell; 25:219-232.

Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills G, Kobayashi R, Hunter T, Lu Z (2007) Phosphorylation of b-catenin by AKT Promotes b -catenin Transcriptional Activity. J Biol Chem. In press.

Program Affiliation:
Program in Cancer Biology