UNMC | David W. Li

Associate Professor, Biochemistry and Molecular Biology

αα David Li, PhD Phone: 402-559-5073 (Office)
402-559-5074 (Lab)
402-541-8012 (Cell)
402-559-6650 (Fax)
Email: davidli@unmc.edu or dwli1688@hotmail.com (Preferred)

Education/Training:
Ph.D. University of Washington, Seattle, WA, 1992.
Postdoctoral Training, Columbia University Medical Center in New York City, NY, 1996.
Associate Professor of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Ne, USA.
Courtesy Associate Professor of Ophthalmology & Visual Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
Honorary Lotus Scholar Professor of Cellular & Developmental Biology, Hunan Normal University, Changsha, Hunan, China.
Honorary Guest Professor of Molecular Medicine, Tianjin Medical University, Tianjin, China.
Honorary Guest Professor of Ophthalmology & Visual Sciences, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Honorary Guest Professor of Medical Sciences, Anhui Medical Center, Anhui Medical University, Hefei, Anhui, China.

Research:

Student Research Opportunities in my Lab
Postdoctoral fellows
Graduate students
Medical students, summer research
Undergraduate students, Summer Research

Primary Research/Clinical Interests/Expertise:
1. Apoptosis in ocular development and diseases, cancer and cardiovascular diseases
2. Signal transduction pathways in eye development, ocular diseases, and carcinogenesis
3. Roles of protein serine/threonine phosphatases and MAP kinases in ocular diseases, cancer, cardiovascular diseases and neural diseases
4. Telomerase functions and human aging
5. Functional mechanisms of alpha-crystallins in the eye, brain and heart

Since joining UNMC in 2006, Dr. David Wan-Cheng Li has brought in several grants from the NIH and other sources, for a total of 2 million dollars, and has published over thirty peer-reviewed research papers. He received the Outstanding Cataract Research Award from the National Foundation for Eye Research in 2006, and the Lotus Scholar Contribution Award from Hunan Province Government, China, in 2009. He is currently the editor-in-chief of Current Molecular Medicine, a journal ranked 16 out of 111 journals in laboratory and experimental medicine with an impact factor of 4.476 in 2011. Dr. Li has been invited as a reviewer of over forty international journals and grants for different organizations. He has also served as an organizer or co-organizer for dozens of national and international symposia or conference sessions. He has trained half a dozen postdoctoral fellows and more than a dozen Ph.D. students since serving as a faculty member. Research in Dr. David Li's laboratory focuses on the molecular and cellular mechanisms of ocular diseases (especially cataractogenesis) and cancer. Currently, the Li lab has been concentrating on the following projects:

Project 1. Functional Mechanisms of Protein Serine/Threonine Phosphatases-1 in the Ocular Lens. (Grants Support: R29EY11372 1996-2002, $598,561; 1R01EY015765 2005-2010, $872,574; Pending 2013 to 2018).

In 1995, we first proposed that stress-induced apoptosis of lens epithelial cells act as a common cellular mechanism for non-congenital cataract formation in human and other vertebrates. Since our initial work, about seven hundred research articles have been published on lens epithelial cell apoptosis and cataractogenesis from many laboratories over the world.

For this project, the first grant (R29EY11372) received from NIH/NEI supported the following important discoveries:

1. The regulatory components mediating apoptotic pathway in the ocular lens system including p53, Bax, Caspase-3;
2. Protein serine/threonine phosphatase-1 (PP-1) is a major phosphatase in the ocular lens, preventing stress-induced apoptosis by oxidative stress and other stress conditions;
3. Among the three major MAP kinases (ERK1/2, JNK1/2 and p38 kinases), expression and activities of ERK1/2 are very high in both young lenses and old human lenses, in both lens epithelium and lens fiber cells;
4. We first demonstrate that the human telomerase catalytic subunit can form functional complexes with the RNA template from rabbit and bovine;
5. Besides the classical role of synthesizing telomere, telomerase can negatively regulate apoptosis, accelerate cell growth via RB-E2F pathway, and suppress lens cell differentiation through the modulation of the RAS/RAF/MEK/ERK signaling pathway;
6. We demonstrate that the anti-proapoptotic gene, Bcl-2, can regulate gene expression through control of the RAS/RAF/MEK/ERK signaling pathway; By repressing expression of αB-crystallin, Bcl-2 lost its anti-apoptotic function;
7. For the first time, we demonstrate that the two α-crystallins display differential abilities to regulate different signal transduction pathways and prevent stress-induced apoptosis;
8. Oxidative stress regulates c-Jun, c-fos and c-myc in lens system to control other genes in the lens, which partially contributes to cataractogenesis.

These results are published in 12 research articles and 2 review articles as listed below:

Mao YW, Liu JP, Xiang H, Li DW. (2004). Human αA- and αB-crystallins bind to Bax and Bcl-X(S) to sequester their translocation during staurosporine-induced apoptosis. Cell Death Differ. 11(5):512-26. PMID: 14752512

Feng H, Xiang H, Mao YW, Wang J, Liu JP, Huang XQ, Liu Y, Liu SJ, Luo C, Zhang XJ, Liu Y, Li DW. (2004). Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes. Oncogene. 23(44):7310-7321. PMID: 15326476

Liu JP, Schlosser R, Ma WY, Dong Z, Feng H, Liu L, Huang XQ, Liu Y, Li DW. (2004). Human αA- and αB-crystallins prevent UVA-induced apoptosis through regulation of PKCα, RAF/MEK/ERK and AKT signaling pathways. Exp Eye Res. 79(3):393-403. Erratum in: Exp Eye Res.79(6):807. Corrected and republished in: Exp Eye Res. 79(6):393-403. PMID: 15669141

Li DW, Liu JP, Wang J, Mao YW, Hou LH. (2003). Expression and activity of the signaling molecules for mitogen-activated protein kinase pathways in human, bovine, and rat lenses. Invest Ophthalmol Vis Sci.44(12):5277-86. PMID: 14638727.

Xiang H, Wang J, Mao Y, Liu M, Reddy VN, Li DW. (2002). Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway. Oncogene. 21(23):3784-3791. PMID: 12032846.

Geissler FT, Li DW, James ER. (2001). Inhibition of lens epithelial cell growth by induction of apoptosis: potential for prevention of posterior capsule opacification. J Ocul Pharmacol Ther. 17(6):587-96. PMID: 11777182.

Li DW, Xiang H, Fass U, Zhang XY.(2001). Analysis of expression patterns of protein phosphatase-1 and phosphatase-2A in rat and bovine lenses. Invest Ophthalmol Vis Sci.42(11):2603-9. PMID: 11581206.

Li DW, Xiang H, Mao YW, Wang J, Fass U, Zhang XY, Xu C. (2001). Caspase-3 is actively involved in okadaic acid-induced lens epithelial cell apoptosis. Exp Cell Res. 266(2):279-91.PMID: 11399056.

Mao YW, Xiang H, Wang J, Korsmeyer S, Reddan J, Li DW. (2001). Human bcl-2 gene attenuates the ability of rabbit lens epithelial cells against H₂O₂-induced apoptosis through down-regulation of the alpha B-crystallin gene. J Biol Chem. 276(46):43435-45.PMID: 11546795.

Xiang H, Wang J, Mao YW, Li DW. (2000). hTERT can function with rabbit telomerase RNA: regulation of gene expression and attenuation of apoptosis. Biochem Biophys Res Commun. 278(3):503-510. PMID: 11095941.

Li DW, Fass U, Huizar I, Spector A. (1998). Okadaic acid-induced lens epithelial cell apoptosis requires inhibition of phosphatase-1 and is associated with induction of gene expression including p53 and bax. Eur J Biochem. 257(2):351-61. PMID: 9826180.

Li DW, Spector A. (1997). Hydrogen peroxide-induced expression of the proto-oncogenes, c-jun, c-fos and c-myc in rabbit lens epithelial cells. Mol Cell Biochem. 173(1-2):59-69. PMID: 9278255

Spector, A., Ho, Y-S., Wang, R-R., Ma, W., Yang, Y. and Li, W-C. (1998) Evaluation of the antiperoxide defense system of the lenses utilizing GSH peroxidase transgenics and knockouts. In Oxidative Stress and Redox Regulation: Cellular Signaling, AIDS, Cancer and Other Diseases. (Montagnier, Olivier and Pasquier, eds). Chapter 48, pp507-515. Marcel Dekker, Inc., New York . (review article).

Li, D. W-C. (1997). The lens epithelium, apoptosis and cataract formation. In Eye Lens Epithelium: Damaging Mechanisms and Lens Transparency. (Glaesser D, Hockwin O and Vrensen GF, eds). Chapter 8, pp81-108. Deutsche Akademic der Naturforscher Leopoldina (German Academy of Natural Sciences), Halle . Nova Acta Leopoldina. NF 75, Nr. 299, 81-108. ISSN 0369-5034. (review article).

The ongoing research on this project was then supported by the second NIH/NEI grant (1R01EY015765), which allowed us to make the significant discoveries as detailed below:

1. The protein serine/threonine phosphatase-1 directly dephosphorylates p53 at Ser- 15, Ser-20, Ser-37 and Ser-46, and other sites to prevent stress-induced apoptosis;
2. Dephosphorylation of p53 at these sites substantially changes its transcriptional activity and proapoptotic ability;
3. We demonstrated for the first time that p53 directly regulates Bak expression to control apoptosis of human lens epithelial cells, and modulation of p53 phosphorylation status by PP-1 affects p53 control of apoptosis through regulation of Bak;
4. The p53-Bak pathway is also involved in control of differentiation of lens epithelial cells through regulation of the p53 stability.
5. Dephosphorylation of p53 at a single residue by PP-1 changes the global expression pattern of more than 80 p53 downstream target genes;
6. We first demonstrate that p53 directly regulates c-Maf and Prox1, two important transcription factors for lens development to control lens differentiation;
7. We show that p53 directly regulates lens crystallin genes to control lens differentiation;
8. The protein serine/threonine phosphatase-2A also directly dephosphorylates p53 at Ser-15 to modulate p53-Bak pathway;
9. We elucidated, for the first time, the molecular mechanism why the ocular lens does not develop natural tumor;
10. We demonstrated that PP-1 directly dephosphorylates Pax-6, an important transcription factor controlling brain and eye development; dephosphorylation of Pax-6 by PP-1 significantly modulates Pax-6 function;
11. We also demonstrate that PP-1 is one the major phosphatases that regulate AKT kinase activity to modulate lens proliferation, differentiation and apoptosis.
12. We first demonstrate that sumoylation plays an important role in regulating lens differentiation

These results are published in 18 research articles and 4 review articles listed below:

M. Deng, P. Chen., F. Liu., S. Fu., H. Tang., Y. Fu., Z. Xiong., S. Hui., W. Ji., X. Zhang., L. Zhang., L. Gong., X. Xu., W. Hu., S. Sun., J. Liu., L. Xiao., W.-B. Liu., Y.-M. Xiao., S. –J. Liu, Y. Liu and D. W.-C. Li (2012). The p53-Bak apoptotic signaling axis plays an essential role in regulating differentiation of the ocular lens. Curr. Mol. Med. 12(8): 901-916.

Fangyuan Liu, Xiang-Cheng Tang, Mi Deng, Weike Ji, Xinyan Zhang, Lili Gong, Jiao Liu, Lan Zhang⁴ Shuming Sun, Kaili Wu, Ming-Xing Wu, Xia-Lin Liu, Ming-Bin Yu, Yizhi Liu, and David W-C Li. (2012). The tumor suppressor p53 directly regulates c-Maf and Prox-1 to control lens differentiation. Curr. Mol. Med. 12(8):917-928.

J Liu, WK Ji, SM Sun, L Zhang, H-G Chen, Y Mao, L Liu, X Zhang, L Gong, M Deng, L Chen, W-J Han, P-C Chen, W-F Hu, XH Hu, JP Liu, Z Woodward, W-B Liu, Y-M Xiao, S-P Liang, Yun Liu S-J Liu and D W-C Li(2012) The PP2A-Aβ gene is regulated by multiple transcriptional factors including Ets-1, SP1/SP3, and RXRα/β. Curr. Mol. Med. 12(8): 982-994.

Cui X, Zhang J, Du R, Wang L, Archacki S, Zhang Y, Yuan M, Ke T, Li H, Li D, Li C, Li DW, Tang Z, Yin Zand Liu M. (2012). HSF4 is involved in DNA damage repair and cataract formation via regulation of rad51. Biochim Biophy Acta 1822(8):1308-1315. PMID:22587838.

Mitchell DC, Brad BA, Liu L, Hu X-H, Huang X-Q, Ji W-K, Chen P-C, Hu W-F, Liu J-P, Liu, Zhang J, Liu M, Li DW-C (2011). GEFT, a rho family guanine nucleotide exchange factor regulates lens differentiation in vertebrate eye. Curr. Mol. Med. 11(6): 465-480.

Zhang L, Sun S, Zhou J, Liu J, Lv JH, Yu XQ, Li C, Gong L, Yan Q, Deng M, Xiao L, Ma H, Liu JP, Peng YL,Wang D, Liao GP, Zou LJ, Liu WB, Xiao YM, Li DW. (2011). Knockdown of Akt1 promotes Akt2 upregulation and resistance to oxidative stress-induced apoptosis through control of multiple signaling pathways. Antioxid Redox Signal. 15(1):1-16. PMID: 21303257

Yan Q, Gong L, Deng M, Zhang L, Sun S, Liu J, Ma H, Yuan D, Chen PC, Hu X, Liu J, Qin J, Xiao L, Huang XQ, Zhang J, Li DW. (2010). Sumoylation activates the transcriptional activity of Pax-6, an important transcription factor for eye and brain development. Proc Natl Acad Sci U S A. 107(49):21034-9. PMID: 21084637.

Xiao L, L Gong, D Yuan, M Deng, X-M Zeng, L Chen, L Zhang, Q Yan, J-P Liu, X-H Hu, S-M Sun, J Liu, H-L Ma, C-B Zheng, H Fu, P-C Chen, J-Q Zhao, S-S Xie, L–J Zou, Y-M Xiao, W-B Liu, J Zhang, Y Liu and Li, DW-C. (2010). Protein phosphatase-1 regulates Akt1 signaling transduction pathway to control gene expression, cell survival and lens differentiation. Cell Death & Differentiation. 17(9):1448-1462. PMID: 20186153.

Mi Deng, Pei-Chao Chen, Sisi Xie, Jun-Qiong Zhao, Lili Gong, Jinping Liu, Lan Zhang, Shuming Sun, Jiao Liu, Haili Ma, Surinder Batra, and Li, D.W.-C. (2010). The small heal shock protein αA-crystallin is expressed in pancreas and acts as a negative regulator of carcinogenesis. Biochem. Biophys. Acta.-Molecular Basis of Diseases. 1802:621-631. PMID: 20434541.

Chen H-G, W-J Han, M Deng, Qin J-C, J-P Liu, D Yuan, Liu J-P, Xiao L, Gong L, Liang S-P, Zhang J, Liu Y and Li D. W-C (2009). Transcriptional regulation of PP2A-Aα is mediated by multiple factors including AP-2α, CREB, ETS, and SP-1. PLoS One. 4(9): e7019. PMID:19750005.

Ma H-L, Y-L Peng, L Gong, W-B Liu, S Sun, J Liu, C-B Zheng, H Fu, D Yuan, J-Q Zhao, P-C Chen, S-S Xie, X-M Zeng, Y-M Xiao, Y Liu and D W-C Li. (2009). The goldfish SG2NA gene encodes two a-type regulatory subunits for PP-2A and displays distinct developmental expression pattern. Gene Regulation & System Biol. 3:115-129. PMID: 19838339.

Qin J-C, He-Ge Chen, Qin Yan, Mi Deng, Liu J-P, S. Doerge, W-Y., Ma, Z. Dong, and Li, D. W-C. (2008). Protein phosphatase-2A is a target of epigallocatechin-3-gallate and modulates the p53-Bak apoptotic pathway. Cancer Res. 68(11):4150-4162. PMID: 18519674.

Liu, W-B, Y Li, L Zhang, H-G Chen, J-P Liu, S-M Sun, Yun Liu and Li, D. W-C (2008). Differential expression of the catalytic subunits for PP-1 and PP-2A and the regulatory subunits for PP–2A in mouse eye. Mol. Vis. 14:762-773. PMID: 18432318.

Yan Q, W-B Liu, J Qin, J-P Liu, H-G Chen, X Huang, L-L Chen, S-M Sun, M Deng, L-L Gong, Y Li, L Zhang, Y Liu, H Feng, Y-M Xiao, Y Liu, and Li DW-C. (2007). Protein phosphatase-1 dephosphorylates Pax-6, a transcription factor controlling brain and eye development. J. Biol. Chem. 282 (19):13954-13965. PMID:17374606.

Mitchell DC, BA Bryan, J-P Liu, Liu WB, Zhang L, Qu J, Zhou X, Liu M, DW-C Li (2007). Developmental expression of three small GTPases in mouse eye. Mol. Vis. 13:1144-1153. PMID: 17653061.

Li, D. W-C., Liu Y, Liu J-P., P.C. Schmid., R. Schelosser, H. Feng, Y-M Xiao, W-B. Liu, Yan Q, Gong L, Sun S-M, Deng M, and Yun Liu (2006). Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities. Oncogene. 25:3006-3022. PMID: 16501611.

Wang J, Feng H, Huang X-Q, Xiang H, Y-W. Mao, Liu J-P, Yan Q, Liu W-B, Liu Y, Deng M, Gong L, Sun S-M, Yun Liu and Li, D. W-C. (2005). hTERT immortalizes bovine lens epithelial cells and suppresses differentiation through regulation of the ERK signaling pathway. J. Biol. Chem. 280: 22776-22787. PMID:15849192

Li, D. W-C., Liu, J-P., Mao Y. W., H. Xiang, J. Wang, W-Y Ma, Z. Dong, H. M. Pike, Rhoderick E. Brown and J. C., Reed (2005). Calcium-activated RAF/MEK/ERK pathway mediates p53-dependent apoptosis and is abrogated by αB-crystallin through inhibition of Ras activation. Mol. Biol. Cell. 16:4437-4453. PMID:16000378

Li, D. W-C., L Gong, M Deng, J-P Liu, M Liu, and Y-W Mao (2010). The two lens structural proteins, αA- and αB-crystallins, prevent stress-induced apoptosis through regulation of multiple signaling transduction pathways. In: Arrigo, Simon (eds). Small Stress Proteins and Human Diseases. Nova Science Publisher, Inc NY, USA. Chapter 1.1 pp89-116. (review article).

Zhang L, Yan Q, Liu J-P, Zou L-J, Liu J, Sun S-M, Deng M, Gong L, Ji W-K, Li D W-C (2010). Apoptosis: its functions and control in the ocular lens. Curr. Mol. Med. 10(9):864-875.

Yan, Q., Mao Y-W and Li, D. W-C. (2009) Protein serine/threonine phosphatases in the nervous system. In: Binder, Hirokawa, Windhorst (eds). Encyclopedia of Neuroscience, Vol. 4. Springer, Heidelberg , pp 3325-3329. (review article).

Yan Q, Liu J-P, Li DW-C. (2006) Apoptosis in lens development and pathology. Differentiation. 74:195-211. (review article).

Currently, we are continuing to work on this project. Support on this project is pending. We are addressing the answers to the following questions regarding PP-1 control of lens differentiation and cataractogenesis in this project:

1. How many residues in p53 are subjected to PP-1 regulation through dephosphorylation and how does dephosphorylation in these residues modulate p53 functions?
2. How do p53 and other major lens transcription factors synergistically regulate lens genes to control lens differentiation?
3. What are other major targets in the ocular lens that can be modulated by PP-1?

Project 2. Functional Mechanisms of Alpha-Crystallins (Grants Support:1R01EY018380, 2009-2012, $1,028,456; Pending 2013-2018).

The ocular lens is constantly exposed to stress conditions and thus lens epithelial cell apoptosis induced by stress factors is inevitable, the lens carries extremely efficient anti-apoptotic system to guard apoptosis. The lens structure proteins, αA- and αB-crystallins, are distinct anti-apoptotic regulators, which protect lens epithelial cells from apoptosis induced by a large number of stress factors as shown first by Dr. AP Arrigo’s laboratory and later by many other laboratories including us. Although it is well established that the two α-crystallins are excellent antiapoptotic regulators, the molecular mechanisms mediating their anti-apoptotic functions remains largely unknown. The project supported by the above grant allow us to study the functional mechanisms of αA- and αB-crystallins. We have demonstrated that αA- and αB-crystallins can regulate apoptosis at multiple signaling steps and targets as summarized below:

1. We demonstrated that αB-crystallin interacts with the procaspase-3 and partially processed procaspase-3 to repress caspase-3 activation;
2. We revealed that α-crystallins can regulate the translocation of the proapoptotic members of the Bcl-2 family from cytoplasm into mitochondria to suppress apoptosis;
3. We demonstrated that in response to UVA-induced apoptosis, αB-crystallin but not αA-crystallin can repress activation of the RAS/RAF/MEK/ERK signaling pathway to resist on the UVA and calcimycin-induced apoptosis;
4. We showed that in response to UVA-induced apoptosis, αA-crystallin helps to activate the PI3K-AKT pathway to resist on the UVA-induced apoptosis;
5. We demonstrated that α-crystallins interact with Caspase-3 and Bax in the developing lens to guard developmental apoptosis;
6. We showed that αB-crystallin regulates GRF2 to control the RAS/RAF/MEK/ERK signaling pathway;
7. We revealed that αA-crystallin is highly expressed in the pancreas besides its abundant expression in lens;
8. We demonstrated that αA-crystallin negatively regulates carcinogenesis in pancreas;
9. We showed that αA-crystallin can regulate TGFbeta signaling pathway.

These results have been published in 10 research articles and 2 review articles:

Gong Lili, Wei-Ke Ji, Wen-Feng Hu, Xiao Hui Hu, Xiao-Wen Chen, Zi-Li Li, Xi Li, Xiang-Ming Lv, Xinyan Zhang, Mi Deng, Pei-Chao Chen, Jinping Liu, Jiao Liu, Shuming Sun, Lan Zhang, Qin Yan, He-Ge Chen, Lili Chen, Eric Wawrousek and Li, D.W.-C. (2012). αA-crystallin negatively regulates p53-mediated intrinsic apoptotic pathway to enhance resistance of ocular pathogenesis. Submitted.

Hu X-H, Liu J-P, Lili Gong, Mi Deng, Qin Yan, He-Ge Chen, Doerge S, Schlosser R, Mi Deng, Lili Gong, Wei-Ya Ma, Zigang Dong and Li, D.W.-C. (2012). Human alphaA- and alphaB-crystallins regulate DNA damaging signaling pathways to attenuate UVA-induced apoptosis. Submitted.

Peichao Chen, Wei-Ke Ji, Fang-yuan Liu, Hong-Jiao Tang, Shujun Fu, Xinyan Zhang, Mugen Liu, Lili Gong, Mi Deng, Wen-Feng Hu, Xiao-Hui Hu, Xiao-Wen Chen, Zi-li Li, Xi Li, Liu J-P, Li D W-C (2012). Alpha-crystallin and carcinogenesis. Curr. Mol. Med. 12(9), 1163-1173.

Wen-Feng Hu, Gong Lili, Zhi-Jun Cao, Haili Ma, Weike Ji, Mi Deng, Mugen Liu, Xiao-Hui Hu, Peichao Chen, Qin Yan, He-Ge Chen, Jiao Liu, Shuming Sun, Lan Zhang, Jinping Liu, Eric Wawrousek, and Li, D.W.-C. (2012). α-Crystallins interact with caspase-3 and Bax to guard mouse lens development. Curr. Mol. Med. 12(2): 177-187.

Li, D. W-C., L Gong, M Deng, J-P Liu,M Liu, and Y-W Mao(2010). The two lens structural proteins, αA- and αB-crystallins, prevent stress-induced apoptosis through regulation of multiple signaling transduction pathways. In: Arrigo, Simon (eds). Small Stress Proteins and Human Diseases. Nova Science Publisher, Inc NY, USA. Chapter 1.1:89-116. (review article).

Li H, C Li, Q. Lu, T Su, T Ke, D W-C Li, M Yuan, J Liu, X Ren, Z Zhang, S Zeng, Q K. Wang and M Liu (2008). Cataract mutation P20S of αB-crystalline impairs chaperone activity of αA-crystallin and induces apoptosis of human lens epithelial cells. Biophy. Biochem. Acta. 1782:303-309.

Li D W-C, Liu J-P, Mao YW, Xiang H, Wang J, Ma WY, Dong Z, Pike HM, Brown RE, Reed JC. (2005). Calcium-activated RAF/MEK/ERK pathway mediates p53-dependent apoptosis and is abrogated by αB-crystallin through Inhibition of Ras Activation. Mol. Biol. Cell. 16:4437-4453.

Mao Y-W, Liu J, Xiang H, Li DW-C. (2004). Human αA and αB-crystallins bind to Bax and Bcl-X_S to sequester their translocation during staurosporine- induced apoptosis. Cell Death and Differ. 11:512-526.

Liu JP, Schlosser R, Ma WY, Dong Z, Feng H, Liu L, Huang XQ, Liu Y, Li DW. (2004). Human αA- and αB-crystallins prevent UVA-induced apoptosis through regulation of PKCalpha, RAF/MEK/ERK and AKT signaling pathways. Exp Eye Res. 79(3):393-403. Erratum in: Exp Eye Res.79(6):807. Corrected and republished in: Exp Eye Res. 79(6):393-403. PMID: 15669141

Li DW-C, Xiang H, Mao YW, Wang J, Fass U, Zhang XY, Xu C. (2001). Caspase-3 is actively involved in okadaic acid-induced lens epithelial cell apoptosis. Exp Cell Res. 266(2):279-91.PMID: 11399056.

Mao YW, Xiang H, Wang J, Korsmeyer S, Reddan J, Li DW-C. (2001). Human bcl-2 gene attenuates the ability of rabbit lens epithelial cells against H₂O₂-induced apoptosis through down-regulation of the αB-crystallin gene. J Biol Chem. 276:43435-45.PMID: 11546795.

Currently, we are studying how α-crystallins regulate these different pathways and signaling targets to prevent lens cell apoptosis and cataractogenesis.

Project 3. Role of Protein Serine/Threonine Phosphatases–2A in Carcinogenesis (Grant Support: W81XWH- 01-1-0474 from DOD, $750,000; PI: Ming-Fong Lin. LI DW-C, Co-Investigator, 5% Efforts).

PP-2A is highly expressed in most cancer cells and modulate many different targets during carcinogenesis. Mutations of the scaffold subunits in PP-2A cause various types of cancer. Our recent work revealed that various transcription factors including Ets-1, CREB, AP-2α and SP-1 regulate PP2A-Aα. Moreover, we demonstrate that PP-2A is a target of the EGCG and PP-2A plays an important role in EGCG-mediated chemoprevention of carcinogenesis.

These results have been published in the following articles:

Currently, we are studying the key targets regulated by PP-2A and exploring how PP-2A regulates carcinogenesis through these targets.

Selected Recent Publications (Total 88):

2012

Gong L, Weike J, Chen C, Liu J, Hu X, Hu WF, Zhang X, Deng M, Liu FY, Tang XC, Liu M, Yan Q, Zhang L, Sun SM, Fu SJ, Li C, Chen XW, Li Z, Li Z, Woodward Z, Wu K, Wu MX, Liu XL, Liu S, Liu YZ, Li D.W.-C. (2012). SUMO1 and SUMO2/3 differentially control lens differentiation through regulation of the transcription factor SP-1. Submitted.

Xiukun Cui, Duanzhuo Li, Mi Deng, Tie Ke, Lei Wang, Wei-Ke Ji, Yuexuan Zhang, Shengjie Liao, Mi Huang, Yuyan Gong, Guohua Yang, Hui Li, Jing Yu Liu, Zhaohui Tang, Xinyan Zhang, Peichao Chen, G. Stanley Cox, David Wan-Cheng Li and Mugen Liu. (2012). HSF4 and p53 are essential for G1/S arrest and lens fiber cell differentiation. Submitted.

C Liu, M Deng, J Xiang, H Ma, W Hu, Y Zhao, DW Li, SP Liang. (2012) A novel spider peptide toxin suppresses tumorigenesis. Curr. Mol. Med. 12(10): In Press.

Li DWC. (2012) Exciting discoveries about new p53 target genes, cancer drugs and diagnostic tools, and mechanisms of various human diseases. Curr. Mol. Med. 12(8):899-900.

W Liu, Q Yan, FY Liu, XC Tang, HG Chen, J Liu, N Lei, XW Zhang, WK Ji, XH Hu, WF Hu, PC Chen, Z Woodward, K Wu, M-X Wu, X-L Liu, L-X Luo, M-B Yu, Y Liu, and D W-C Li. (2012) The protein serine/threonine phosphatase-1 is essential in governing normal development of vertebrate eye. Curr. Mol. Med. 12(10); In Press.

F. Liu, X-C. Tang, M Deng, WK Ji, XY Zhang, L Gong, J Liu, L Zhang, S Sun, K Wu, M-X Wu, X-L Liu, M-B Yu, Y Liu, and D.W-C Li. (2012). The tumor suppressor p53 directly regulates c-Maf and Prox-1 to control lens differentiation. Curr. Mol. Med. 12(8):917-928.

M. Deng, P. Chen., F. Liu., S. Fu., H. Tang., Y. Fu., Z. Xiong., S. Hui., W. Ji., X. Zhang., L. Zhang., L. Gong., X. Xu., W. Hu., S. Sun., J. Liu., L. Xiao., W.-B. Liu., Y.-M. Xiao., S. –J. Liu, Y. Liu and D. W.-C. Li (2012). The p53-Bak apoptotic signaling axis plays an essential role in regulating differentiation of the ocular lens. Curr. Mol. Med. 12(8): 901-916.

Cui X, Zhang J, Du R, Wang L, Archacki S, Zhang Y, Yuan M, Ke T, Li H, Li D, Li C, Li DW-C, Tang Z, Yin Zand Liu M. (2012). HSF4 is involved in DNA damage repair and cataract formation via regulation of rad51. Biochim Biophy Acta 1822(8):1308-1315. PMID:22587838.

2011

Liu W-B, Nie Lei, Hui Shan-Shan, Hu Xiao-Hui, Ma Hui, Wang Ling, Xiao Ya-Mei, D W-C Li. (2011). Study on differential expression and distribution of the catalytic subunits for PP-1 in the different tissues of mouse. Chinese J Biochem. Mol. Biol. 27 (5):437-443.

Zhao Jun-Qiong, Xie Si-Si, Chen Pei-Chao, Zou Li-Jun, Liu Wen-Bin, Xiao Ya-Mei, Liu Shao-Jun, Liu Yun and David Wan-Cheng Li. (2011). Molecular cloning and differential expression patterns of the gene encoding the PR55g of PP-2A in goldfish, carassius auratus. Acta Hydrobiologica Sinica. 35(3):482-488.

2010

Xiao L, Gong LL, Yuan D, Deng M, Zeng XM, Chen LL, Zhang L, Yan Q, Liu JP, Hu XH, Sun SM, Liu J, Ma HL, Zheng CB, Fu H, Chen PC, Zhao JQ, Xie SS, Zou LJ, Xiao YM, Liu WB, Zhang J, Liu Y, Li DW-C. (2010). Protein phosphatase-1 regulates Akt1 signal transduction pathway to control gene expression, cell survival and differentiation. Cell Death Differ. 17(9):1448-1462. PMID: 20186153.

Deng M, Chen PC, Xie S, Zhao J, Gong L, Liu J, Zhang L, Sun S, Liu J, Ma H, Batra SK, Li DW-C. (2010). The small heat shock protein αA-crystallin is expressed in pancreas and acts as negative regulator of carcinogenesis. Biochim Biophys Acta-Molecular Basis of Diseases. 1802:621-631. PMID: 20434541.

Xiao Y-M, Chen L, Liu J, Zou L-J, Liu W-B, Chen H-G, Liu Y, Li D W-C. (2010). JNK1 downregulation is associated with sex reversal of the ricefield eel. J. Exp. Zool. (Mol. Dev. Evol.). 314B(3):242-256. PMID: 19838339.

Gong Lili and David W. Li (2010). SUMOylation in ocular development and pathology. Curr. Mol. Med. 10(9):794-801.

Zhang L, Yan Q, Liu J-P, Zou L-J, Liu J, Sun S-M, Deng M, Gong L, Ji W-K, Li D W-C (2010). Apoptosis: Its functions and control in the ocular lens. Curr. Mol. Med. 10(9):864-875.

Li, D. W-C., L Gong, M Deng, J-P Liu, M Liu, and Y-W Mao (2010). The two lens structural proteins, αA- and αB-crystallins, prevent stress-induced apoptosis through regulation of multiple signaling transduction pathways. In: Arrigo, Simon (eds). Small Stress Proteins and Human Diseases. Nova Science Publisher, Inc NY, USA. Chapter 1.1 pp89-116.

Zhao J-Q, S-S Xie, W-B Liu, Y-M Xiao, X-M Zeng, M Deng, L Gong, J-P Liu, P-C Chen, J Zhou, X-H Hu, J-H Lv, X-Q Yu, D Wang, C Li, Y-L Peng, G-P Liao, Y Liu, DW-C Li. (2010). Molecular cloning of the genes encoding the PR55/Bβδ regulatory subunits for PP-2A and analysis of their functions in regulating development of goldfish, Carassius auratus. Gene Regulation and System Biology. 4:135-148.

Liu W-B, Hu X-H, Hui S-S, J Zhou, J Liu, Y-M Xiao, S-J Liu, D W-C Li. (2010). Differential expression patterns of the catalytic subunits for PP-1 and PP-2A in the ocular tissue of goldfish, carassius auratus. Chinese J Biochem. Mol. Biol. 26 (12):1135-1142.

2009

Chen H-G, Han W-J, Deng M, Qin J-C, Yuan D, Liu J-P, Xiao L, Gong L, Liang S-P, Zhang J, Liu Y and Li D. W-C (2009). Transcriptional regulation of PP2A-Aα is mediated by multiple factors including AP-2α, CREB, ETS, and SP-1. PLoS One. 4(9): e7019. doi:10.1371/journal.pone.0007019.PMID: 19750005.

Ma H-L, Peng Y-L, Gong L, Liu W-B, Sun S, Liu J, Zheng C-B, Hu F, Yuan D, Zhao J, Chen PC, Xie SS, Zeng XM, Xiao YM, Liu Yand Li DW-C. (2009). The goldfish SG2NA gene encodes two α-type regulatory subunits for PP-2A and displays distinct developmental expression pattern. Gene Regulation and System Biology. 3:115-129.PMID: 19838339

Fu H, Ma HL, Zheng CB, Lu JH, Yu XG, Li C, Peng YL, Liao GP, Liu WB, Xiao YM, Liu Y and Li DW-C. (2009). Molecular cloning and differential expression patterns of the regulatory subunit B’ of PP-2A in goldfish, carassius auratus. Sci China Ser C-Life Sci. 52(8):724-732. PMID: 19727590.

Yan Q, Mao Y-W, Li DW-C. (2009) Protein serine/threonine phosphatases in the nervous system. In: Binder, Hirokawa, Windhorst (eds). Encyclopedia of Neuroscience, Vol. 4. Springer, Heidelberg , pp 3325-3329.

2008

Qin J-C, Chen H-G, Yan Y, Deng M, Liu J-P, Doerge S, Ma W-Y, Dong Z, and Li DW-C. (2008). Protein phosphatase-2A is a target of EGCG and modulates the p53-Bak apoptotic pathway. Cancer Res. 68:4150-4162.

Liu W-B, Y Li, L Zhang, H-G Chen, J-P Liu, S-M Sun, Y Liu and Li D. W-C (2008). Differential expression of the catalytic subunits for PP-1 and PP-2A and the regulatory subunits for PP–2A in mouse eye. Mol. Vis. 14:762-773.

Selected Publications Before 2008:

Mitchell DC, Bryan BA, Liu J-B, Liu W-B, Zhang L, Qu J, Zhou X, Liu M, Li DW-C (2007). Developmental expression of three small GTPases in mouse eye. Mol. Vis.13:1144-1153.

Li D W-C, Liu J-P, Schmid PC, Schlosser R, Feng H, Liu W-B, Yan Q, Gong L, Sun S-M, Deng M, Liu Y (2006). Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities. Oncogene. 25:3006-3022.

Yan Q, Liu J-P, Li D W-C. (2006) Apoptosis in lens development and pathology. Differentiation. 74:195-211.

Wang J, Feng H, Huang X-Q, Xiang H, Y-W. Mao, Liu J-P, Yan Q, Liu W-B, Liu Y, Deng M, Gong L, Sun S-M, Liu Y, Li DW-C. (2005). hTERT immortalizes bovine lens epithelial cells and suppresses differentiation through regulation of the ERK signaling pathway. J. Biol. Chem. 280:22776-22787.

Huang X-Q, Wang J, Liu J-P, Feng H, Yan Q, Liu W-B, Liu Y, Sun S-M,Deng M, Gong L, Yun Liu and Li, D. W-C. (2005). hTERT extends proliferative lifespan and prevents replicative senescence and oxidative stress-induced apoptosis in human lens epithelial cells. Invest. Ophthalmol. Vis. Sci. 46:5203-5213.

Mao Y-W, Liu J, Xiang H, Li DW-C. (2004). Human αA and αB-Crystallins Bind to Bax and Bcl-X_S to sequester their translocation during staurosporine-induced apoptosis. Cell Death and Differ. 11:512-526.

Feng H, Xiang H, Mao Y-W, Wang J, Liu J-P, Huang X-Q, Liu Y, Liu S-J, Luo C, Zhang X-J, Liu Y, Li DW-C. (2004). Human Bcl-2 activates RAF/MEK/ERK pathway and regulates AP-1 activity and downstream genes in rabbit lens epithelial cells. Oncogene.23:7310-7321.

Liu J-P, Schlosser R, Ma W-Y, Dong Z, Feng H, Liu L, Huang X-Q, Liu Y, Li DW-C. (2004).Human αA- and αB-crystallins prevent UVA-induced apoptosis through regulation of PKCα, RAF/MEK/ERK and AKT signaling pathways. Exp Eye Res. 79:493-503.

Xiang, H., J. Wang, Y-W. Mao, M. Liu, V. Reddy, and Li, D.W-C. (2002). Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway. Oncogene. 21:3784-3791

Mao, Y-W., H. Xiang, J. Wang., S. Korsmeyer, J. Reddan, and D. W-C. Li. (2001). Human Bcl-2 gene attenuates the ability of rabbit lens epithelial cells against H₂O₂-induced apoptosis through down-regulation the alpha B crystallin gene. J. Biol. Chem. 276:43435-43445.

Li WC, Spector A. (1996). Lens epithelial cell apoptosis is an early event in the development of UVB-induced cataract. Free Radic Biol Med. 20:301-11. PMID: 8720900

Li, W-C., Kuszak, J.R., Dunn, K., Wang, R-R., Ma, W-C., Wang, G-M., Spector, A., Leib. M., Cotliar, A.M., Weiss, M., Espy, J., Howard, G., Farris, R.L., Auran, J., Donn, A., Hofeldt, A., Mackay, C., Merriam, J., Mittl, R., and Smith, T.R. (1995) Lens epithelial cell apoptosis appears to be a common cellular basis for non-congenital cataract formation in humans and animals. J. Cell Biol. 130:169-181.

Li, W-C. and L. M. Riddiford (1994) The two duplicated insecticyanin genes, ins-α and ins-β are differentially expressed in the tobacco hornworm, Manduca sexta. Nucleic Acids Res. 22:2945-2950.

Current Funding:

NIH/NEI
Regulation of apoptotic signaling pathways by Alpha-crystallins in the ocular lens
2009-2012

Hunan Normal University
Apoptosis in animal development and human diseases
7/1/2012 - 6/30/2013