Donna Zhang, PhD

Professor
Department(s): 
Pharmacology & Toxicology
dzhang@pharmacy.arizona.edu
520-626-9918

FAX: 520-626-2466
Pharmacy (Skaggs) Building 409

My laboratory has four major research projects. Each of these projects attempts to increase our understanding of how the Nrf2-mediatated antioxidant response is activated, and how to use this knowledge to identify/develop Nrf2-targeting compounds for disease intervention, thus improving human health.

Project 1: Mechanistic studies of the Nrf2/Keap1 signaling pathway
Oxidative stress, an imbalance between production and removal of reactive oxygen species, can damage biological macromolecules including DNA, proteins and lipids (1). Oxidative damage to biological macromolecules can have profound effects on cellular functions and has been implicated in cancer, inflammation, neurodegenerative diseases, cardiovascular diseases and aging. Eukaryotic cells have evolved anti-oxidant defense mechanisms to neutralize reactive oxygen species (ROS) and maintain cellular redox homeostasis. One of the most important cellular defense mechanisms against ROS and electrophilic intermediates is mediated through the ARE (antioxidant responsive element, or electrophile responsive element) sequence in the promoter regions of phase II and antioxidant genes. The ARE-dependent cellular defense system is controlled by the transcription factor Nrf2. Recent advances in the mechanistic studies of this pathway have provided the following models for Nrf2 regulation: Keap1, a key player in the activation of this pathway, has been identified to function as a molecular switch to turn on and off the Nrf2-mediated antioxidant response. Under basal condition, Keap1 is in the off position and functions as an E3 ubiquitin ligase, constantly targeting Nrf2 for ubiquitination and degradation. As a consequence, the constitutive levels of Nrf2 are very low. The switch is turned on when oxidative stress or chemopreventive compounds inhibit the activity of the Keap1-Cul3-Rbx1 E3 ubiquitin ligase, resulting in increased levels of Nrf2 and activation of its downstream target genes. The switch is turned off again upon recovery of cellular redox homeostasis; Keap1 travels into the nucleus to remove Nrf2 from the ARE. The Nrf2-Keap1 complex is then transported out of the nucleus by the nuclear export signal (NES) in Keap1. In the cytosol, the Nrf2-Keap1 complex associates with the Cul3-Rbx1 core ubiquitin machinery, resulting in degradation of Nrf2. We are currently working on the detailed steps of the Nrf2-Keap1-ARE pathway in response to oxidative stress and to chemopreventive compounds.

Project 2: The protective role of Nrf2 in arsenic-induced toxicity and carcinogenicity
Another direction of our research is to understand the molecular mechanisms of toxicity/carcinogenicity of environmental pollutants and the endogenous cellular defense systems to cope with pollutants. Drinking water contaminated with arsenic is a worldwide public health issue. Arsenic has been classified as a human carcinogen that induces tumors in the skin, lung, and bladder. Arsenic damages biological systems through multiple mechanisms, one of them being reactive oxygen species. The ARE-Nrf2-Keap1 signaling pathway, activated by compounds possessing anti-cancer properties, has been clearly demonstrated to have profound effects on tumorigenesis. More significantly, Nrf2 knockout mice display increased sensitivity to chemical toxicants and carcinogens and are refractory to the protective actions of chemopreventive compounds. Therefore, we hypothesize that activation of the ARE-Nrf2-Keap1 pathway acts as an endogenous protective system against arsenic-induced toxicity and carcinogenicity. The following Specific Aims are intended to further elucidate the mechanism of Nrf2-activation in protecting against arsenic-induced toxicity/tumorigenicity. We will (1) determine the protective role of the ARE-Nrf2-Keap1 pathway in arsenic-induced toxicity and cell transformation using an immortalized human bladder urothelial cell line UROtsa, (2) define the molecular mechanisms of activation of the ARE-Nrf2-Keap1 pathway by arsenic, sulforaphane, and tert-butylhydroquinone (tBHQ), and (3) define the protective role of the ARE-Nrf2-Keap1 pathway in arsenic-induced toxicity and tumorigenicity using Nrf2 knockout mouse as a model.

So far, we have demonstrated a protective role of Nrf2 against arsenic-induced toxicity using cell culture and Nrf2-/- mouse model. We have provided evidence demonstrating that Nrf2 protects against liver and bladder injury in response to six weeks of arsenic exposure in a mouse model. Nrf2−/− mice displayed more severe pathological changes in the liver and bladder, compared to Nrf2+/+ mice. Furthermore, Nrf2−/− mice were more sensitive to arsenic-induced DNA hypomethylation, oxidative DNA damage, and apoptotic cell death. Recently, we submitted another manuscript to Toxicological and Applied Pharmacology, reporting our long-term study of the effect of Nrf2 on arsenic-mediated cell transformation and tumor formation. In this study, we provide evidence demonstrating the importance of Nrf2 activation in preventing the carcinogenetic effects induced by long-term exposure to low-dose arsenic both in vitro and in vivo. The UROtsa cell line was used to show that daily exposure to the Nrf2 inducer, tBHQ, alleviated arsenic-induced hypomethylation and cell transformation. Moreover, tBHQ treatment reduced tumorigenicity of arsenic-transformed cells in SCID mice. Chronic treatment with arsenic also compromised the Nrf2-dependent defense response in the bladder epithelium in Nrf2+/+ implicating the important role of Nrf2 in protecting against arsenic-induced carcinogenicity. This study supports the advantages of using dietary supplements specifically targeting Nrf2 as a chemopreventive strategy to protect humans from various environmental insults that may occur on a daily basis.

Project 3: Identification and development of Nrf2 activators into dietary supplements/ for disease prevention Identification and development of Nrf2 inhibitors into therapeutic drugs to enhance the efficacy of cancer treatment
High-throughput screening of Nrf2 activators or inhibitors: we are screening a chemical library and a natural product library to identify compounds that are able to activate or inhibit ARE-luciferase activity using a stable cell line established in our laboratory, MDA-MB-231-ARE-Luc.

Based on the critical role of Nrf2 in disease prevention, using Nrf2 activators to boost our antioxidant response represents an innovative strategy to enhance resistance to environmental insults. Once Nrf2 activators are identified and the specificity of these compounds in activating Nrf2 is validated, the compounds will then be tested for the mechanism by which they confer cellular protection and the feasibility of using these compounds for disease prevention using various disease models.

On the other hand, recent findings point to the “dark side” of Nrf2, as studies have shown that Nrf2 promotes cancer formation and contributes to chemoresistance. Using a genetic approach, we have provided evidence that the level of Nrf2 correlates well with cancer cell resistance to several therapeutic drugs, demonstrating that Nrf2 is likely responsible for chemoresistance. More recently, we have reported a study on Nrf2 expression in endometrial cancer patients (117 cases). We found no detectable Nrf2 expression in complex hyperplasia, 28% Nrf2 positive cases in endometrial endometrioid carcinoma (type I), and 89% Nrf2 positive cases in endometrial serous carcinoma (type II). Please note that type II endometrial cancer is the most malignant and recurrent carcinoma among various female genital malignancies. Furthermore, inhibition of Nrf2 by overexpressing Keap1 sensitized SPEC-2 cells, which are derived from type II endometrial cancer, or SPEC-2 xenografts to cisplatin using both cultured cells and SCID mouse models. These studies demonstrate that Nrf2 contributes to chemoresistance in many cancers originating from different organs and illustrate the urgent need for identification of Nrf2 inhibitors and for the development of Nrf2 inhibitors into druggable compounds to enhance the efficacy of cancer treatment.

We have identified the very first Nrf2 inhibitor and characterized its use to sensitize cancer cells to chemotherapy. The major obstacle in cancer treatment is the resistance of cancer cells to chemotherapy. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive to cancer cell survival. We have identified BB as a selective Nrf2 inhibitor that is able to sensitize cancer cells and xenografts to chemotherapeutic drugs by enhancing the degradation of Nrf2 and inhibiting the Nrf2-dependent antioxidant response. These results suggest that BB can be developed into an adjuvant drug to enhance the efficacy of cancer treatments. The importance of this project: (i) the use of an Nrf2 inhibitor to enhance the efficacy of cancer therapeutics represents a novel approach to caner treatment. Nrf2 inhibitors may be used in a broad spectrum across many types of cancers and chemotherapeutic drugs to increase the effectiveness of cancer treatment. Development of BB into an adjuvant for clinical use to sensitizer many cancer types to treatment will have an enormous impact on human health worldwide. (ii) BB will be extremely useful for the mechanistic investigation of Nrf2 regulation by complex cellular networks.

Project 4: Cross talk between the Nrf2 signaling pathway and others
During the last couple of years, crosstalk between the Nrf2 pathway and other important pathways has emerged. Our group has identified two separate branches that converge with the Nrf2 pathway, the p53-p21(Cip1/WAF1) pathway and the autophagy pathway. Crosstalk is mediated by the direct interaction between p21 and Nrf2, and Keap1 with p62, respectively. In the p53-p21 study, we provide molecular and genetic evidence suggesting that the previously suggested antioxidant function of p53 or p21 is mediated through activation of the Nrf2 pathway. Mechanistically, p21 is able to stabilize Nrf2 by competing away Keap1, thus, activating the Nrf2-mediated antioxidant response. Therefore, the interaction between Nrf2 and p21 represents a fine-tuning mechanism between life and death according to the level of stress. In the study with p62 and Nrf2, we reported a novel mechanism of Nrf2 activation by autophagy deficiency through a direct interaction between Keap1 and p62. In response to stress, cells can utilize several cellular processes, such as autophagy, a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1-dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a non-canonical cysteine-independent mechanism. These work was published in Molecular Cell and Molecular and Cellular Biology, respectively, both are high profile journals. Furthermore, both articles were highlighted in Molecular Cell and Science Signaling, respectively, indicating the importance and high impact of the projects

 

Education: 

PhD 1991-1997 Molecular Toxicology/Oncology New York University
PD 1997-1998 DuPont-Haskell Laboratories Newark, DE

Publications

79. Wu T, Zhao F, Gao B, Tan C, Yagishita N, Nakajima T, Wond PK, Chapman E, Fang D, and Zhang DD. 2014. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev 28(7):708-722. PMID: 24636985

78. Riahi R, Wang S, Long M, Li N, Chiou PY, Zhang DD, Wong PK. 2014. Mapping Photothermally induced gene expression in living cells and tissues by nanorod-locked nucleic acid complexes. ACS Nano 8(4):3597-3605. PMID: 24645754

77. Bao LJ, Jaramillo MC, Zhang ZB, Zheng YX, Yao M, Zhang DD, Yi XF. 2014. Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma. Int J Clin Exp Pathol. 7(4):1502-1513. PMID: 24817946

76. Shen T, Chen XM, Harder B, Long M, Wang XN, Lou HX, Wondrak, GT, Ren DM, Zhang DD. 2014. Plant extracts of the family Lauraceae: a potential resouce for chemopreventive agents that activate the nuclear factor-erythroid 2-related factor 2/antioxidant response element pathway. Planta Med 80(5):426-434. PMID: 24585092

75. Tao S, Justiniano R, Zhang DD, Wondrak GT. 2013. The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV. Redox biology 1:532-541.PMID: 24273736

74. Jiang T, Tian F, Zheng H, Whitman, SA, Lin Y, Zhang X, Zhang N, Zhang DD. 2013. Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response. Kidney Int 82(2):333-343. PMID: 24025640

73. Riahi R, Long M, Yang Y, Dean Z, Zhang DD, Slepian MJ, Wong PK. 2014. Single cell gene expression analysis in injury-induced collective cell migration. Integrative biology 6(2):192-202.PMID: 24336811

72. Wu T, Wang XJ, Tian W, Jaramillo MC, Lau A, Zhang DD. 2014. Poly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription. Free Radic Biol Med 67:69-80. PMID: 24140708

71. Qiao S, Tao S, Rojo de la Vega M, Park SL, Vonderfecht AA, Jacobs SL, Zhang DD, Wondrak GT. 2013. The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death. Autophagy 9:2087-2102. PMID: 24113242

70. Jaramillo MC, Zhang DD. 2013. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 27(20):2179-2191. PMID: 24142871

69. Whitman SA, Long M, Wondrak GT, Zheng H, Zhang DD. 2013. Nrf2 modulates contractile and metabolic properties of skeletal muscle in streptozotocin-induced diabetic atrophy. Exp Cell Res 319(17):2673-2683. PMID: 23896025

68. Qiu Q, Zheng Z, Chang L, Zhao YS, Tan C, Dandekar A, Zhang Z, Lin Z, Gui M, Li X, Zhang T, Kong Q, Li H, Chen S, Chen A, Kaufman RJ, Yang WL, Lin HK, Zhang DD, Perlman H, Thorp E, Zhang K, Fang D.2013. Toll-like receptor-mediated IRE1alpha activation as a therapeutic target for inflammatory arthritis. EMBO J32(18):2477-2490. PMID: 23942232

67. Chen W, Wang H, Tao S, Zheng Y, Wu W, Lian F, Jaramillo M, Fang D, Zhang DD. 2013. Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival. Cell Cycle 12(14):2321-2328. PMID: 23797580

66. Villeneuve NF, Tian W, Wu T, Sun Z, Lau A, Chapman E, Fang D, Zhang DD.2013. USP15 Negatively Regulates Nrf2 through Deubiquitination of Keap1. Mol Cell 51(1):68-79. PMID: 23727018

65. Ji L, Li H, Gao P, Shang G, Zhang DD, Zhang N, Jiang T.2013. Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. PLoS One 8:e63404.P MID: 23667609

64. Riahi R, Dean Z, Wu TH, Teitell MA, Chiou PY, Zhang DD, Wong PK. 2013. Detection of mRNA in living cells by double-stranded locked nucleic acid probes. Analyst 138(17):4777-4785. PMID: 23772441

63. Lau A, Zheng Y, Tao S, Wang H, Whitman SA, White E, Zhang DD. 2013. Arsenic Inhibits Autophagic Flux, Activating the Nrf2-Keap1 Pathway in a p62-Dependent Manner. Mol Cell Biol 33:2436-2446. PMID: 23589329

62. Lu Y, Gao J, Zhang DD, Gau V, Liao JC, Wong PK. 2013. Single cell antimicrobial susceptibility testing by confined microchannels and electrokinetic loading. Anal Chem 85:3971-3976. PMID: 23445209

61. Wu W, Qiu Q, Wang H, Whitman SA, Fang D, Lian F, Zhang DD. 2013. Nrf2 is crucial to graft survival in a rodent model of heart transplantation. Oxid Med Cell Longev 2013:919313. PMID: 23533698      

60#. Tao S, Zheng Y, Lau A, Jaramillo MC, Chau BT, Lantz RC, Wong PK, Wondrak GT, Zhang DD. 2013. Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo. Antioxid Redox Signal 19(14):1647-1661. PMID: 23394605

#(This paper was highlighted as the top story in Pulmonary Cell News 2.06. February 14, 2013).

59. Zhang DD. 2013. Bardoxolone Brings Nrf2-Based Therapies to Light. Antioxid Redox Signal 19(5):517-518. PMID: 23227819

58. Lau A, Whitman SA, Jaramillo MC, Zhang DD. 2013. Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway. J Biochem Mol Toxicol 27:99-105. PMID: 23188707

57.Lau A, Tian W, Whitman SA, Zhang DD. 2013. The predicted molecular weight of nrf2: it is what it is not. Antioxid Redox Signal 18:91-93. PMID: 22703241 (12 citations)

56. Zheng Y, Tao S, Lian F, Chau BT, Chen J, Sun G, Fang D, Lantz RC, Zhang DD. 2012. Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response. Toxicol Appl Pharmacol 265:292-299. PMID: 22975029 (6 citations)

55. Wang F, Tian F, Whitman SA, Zhang DD, Nishinaka T, Zhang N, Jiang T. 2012. Regulation of transforming growth factor beta1-dependent aldose reductase expression by the Nrf2 signal pathway in human mesangial cells. Eur J Cell Biol 91:774-781. PMID: 22951256 (5 citations)

54. Bray K, Mathew R, Lau A, Kamphorst JJ, Fan J, Chen J, Chen HY, Ghavami A, Stein M, DiPaola RS, Zhang DD, Rabinowitz JD, White E. 2012. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS One 7:e41831. PMID: 22848625 (24 citations)

53.Chen W, Jiang T, Wang H, Tao S, Lau A, Fang D, Zhang DD. 2012. Does Nrf2 contribute to p53-mediated control of cell survival and death? Antioxid Redox Signal 17:1670-1675. PMID: 22559194 (10 citations)

52. Riahi R, Yang Y, Zhang DD, Wong PK. 2012. Advances in wound-healing assays for probing collective cell migration. J Lab Autom 17:59-65. PMID: 22357609 (13 citations)

51. Ma J, Cai H, Wu T, Sobhian B, Huo Y, Alcivar A, Mehta M, Cheung KL, Ganesan S, Kong AN, Zhang DD, Xia B. 2012. PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol Cell Biol 32:1506-1517. PMID:22331464 (23 citations)

50. Lin Z, Yang H, Kong Q, Li J, Lee SM, Gao B, Dong H, Wei J, Song J, Zhang DD, Fang D. 2012. USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Mol Cell 46:484-494. PMID:22542455 (28 citations)

49. Hu Q, Zhang DD, Wang L, Lou H, Ren D. 2012. Eriodictyol-7-O-glucoside, a novel Nrf2 activator, confers protection against cisplatin-induced toxicity. Food Chem Toxicol 50:1927-1932. PMID: 22465804 (5 citations)

48#. Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD. 2011. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60:3055-3066. PMID:22025779 (73 citations)

#(This paper was featured by Judy B. de Haan in the same issue 2683-4. PMID: 22025774).

47. Sun Z, Wu T, Zhao F, Lau A, Birch CM, Zhang DD. 2011. KPNA6 (Importin {alpha}7)-mediated nuclear import of Keap1 represses the Nrf2-dependent antioxidant response. Mol Cell Biol 31:1800-1811. PMID: 21383067 (21 citations)

46. Kong S, Kim SJ, Sandal B, Lee SM, Gao B, Zhang DD, Fang D. 2011. The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation. J Biol Chem 286:16967-16975. PMID: 21454709 (27 citations)

45. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, Zhang DD. 2011. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A 108:1433-1438. PMID: 21205897 (67 citations)

44. Chen N, Yi X, Abushahin N, Pang S, Zhang DD, Kong B, Zheng W. 2010. Nrf2 expression in endometrial serous carcinomas and its precancers. Int J Clin Exp Pathol 4:85-96. PMID: 21228930 (13 citations)

43. Chen CH, Gau V, Zhang DD, Liao JC, Wang FY, Wong PK. 2010. Statistical metamodeling for revealing synergistic antimicrobial interactions. PLoS One 5:e15472. PMID: 2988685 (3 citations)

42. Villeneuve NF, Lau A, Zhang DD. 2010. Regulation of the nrf2-keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal 13:1699-1712. PMID:20486766 (84 citations)

41. Zhang DD. 2010. The Nrf2-Keap1-ARE signaling pathway: the regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal. PMID:20486759 (60 citations)

40. Wondrak GT, Villeneuve NF, Lamore SD, Bause AS, Jiang T, Zhang DD. 2010. The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules 15:3338-3355. PMID:20657484 (38 citations)

39. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, Zhang DD. 2010. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res 70:5486-5496. PMID: 20530669 (74 citations)

38#. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD. 2010. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30:3275-3285. PMID: 20421418 (127 citations)

#(This paper was highlighted in the editor’s choice in Science Signaling 3(128):199).

37. Hur W, Sun Z, Jiang T, Mason DE, Peters EC, Zhang DD, Luesch H, Schultz PG, Gray NS. 2010. A small-molecule inducer of the antioxidant response element. Chem Biol 17:537-547. PMID:20534351 (28 citations)

36. Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD. 2010. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59:850-860. PMID:20103708 (99 citations)

35. Chen CH, Lu Y, Sin ML, Mach KE, Zhang DD, Gau V, Liao JC, Wong PK. 2010. Antimicrobial susceptibility testing using high surface-to-volume ratio microchannels. Anal Chem 82:1012-1019. PMID:2821038 (49 citations)

34. Villeneuve NF, Sun Z, Chen W, Zhang DD. 2009. Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels. Cell Cycle 8:3255-3256. PMID:19806015 (22 citations)

33. Chen A, Gao B, Zhang J, McEwen T, Ye SQ, Zhang DD, Fang D. 2009. The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination. Mol Cell Biol 29:5348-5356. PMID:19651900 (14 citations)

32. Sun Z, Huang Z, Zhang DD. 2009. Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS One 4:e6588. PMID:19668370 (76 citations)

31#.Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD. 2009. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell 34:663-673. PMID:19560419 (153 citations)

#(This paper was featured by Michel B. Toledano in the same issue 637-639. PMID: 19560415).

30. Gidwani V, Riahi R, Zhang DD, Wong PK. 2009. Hybridization kinetics of double-stranded DNA probes for rapid molecular analysis. Analyst 134:1675-1681. PMID: 20448937 (12 citations)

29. Jiang T, Huang Z, Chan JY, Zhang DD. 2009. Nrf2 protects against As(III)-induced damage in mouse liver and bladder. Toxicol Appl Pharmacol 240:8-14. PMID:19538980 (49 citations)

28. Zhao F, Wu T, Lau A, Jiang T, Huang Z, Wang XJ, Chen W, Wong PK, Zhang DD. 2009. Nrf2 promotes neuronal cell differentiation. Free Radic Biol Med 47:867-879. PMID:19573594 (32 citations)

27. Wang XJ, Zhang DD. 2009. Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level. PLoS One 4:e5492. PMID:19424503 (13 citations)

26. Sun Z, Chin YE, Zhang DD. 2009. Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol 29:2658-2672. PMID:19273602 (85 citations)

25. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. 2008. Dual roles of Nrf2 in cancer. Pharmacol Res 58:262-270. PMID:18838122 (276 citations)

24. Wang Z, Gidwani V, Zhang DD, Wong PK. 2008. Separation-free detection of nuclear factor kappa B with double-stranded molecular probes. Analyst 133:998-1000. PMID: 18645638 (14 citations)

23. Du Y, Villeneuve NF, Wang XJ, Sun Z, Chen W, Li J, Lou H, Wong PK, Zhang DD. 2008. Oridonin confers protection against arsenic-induced toxicity through activation of the Nrf2-mediated defensive response. Environ Health Perspect 116:1154-1161. PMID:18795156 (50 citations)

22. Wang Z, Gidwani V, Sun Z, Zhang DD, and Wong PK. 2008. Development of a molecular assay for rapid screening of chemopreventive compounds targeting Nrf2. J Lab Autom13: 243-248.  (11 citations)

21. Meserve D, Wang Z, Zhang DD, Wong PK. 2008. A double-stranded molecular probe for homogeneous nucleic acid analysis. Analyst 133:1013-1019.PMID: 18645642 (20 citations)

20. Wondrak GT, Cabello CM, Villeneuve NF, Zhang S, Ley S, Li Y, Sun Z, Zhang DD. 2008.  Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress. Free Radic Biol Med 45:385-395. PMID:18482591 (37 citations)

19. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD. 2008. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235-1243. PMID:18413364 (193 citations)

18. Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD. 2008. Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction. Toxicol Appl Pharmacol 230:383-389. PMID:18417180 (57 citations)

17. Gao B, Lee SM, Chen A, Zhang J, Zhang DD, Kannan K, Ortmann RA, Fang D. 2008. Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Rep 9:480-485. PMID: 18369366 (27 citations)

16. Wang XJ, Sun Z, Chen W, Eblin KE, Gandolfi JA, Zhang DD. 2007. Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity. Toxicol Appl Pharmacol 225:206-213. PMID:17765279 (58 citations)

15. Sun Z, Zhang S, Chan JY, Zhang DD. 2007. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 27:6334-6349. PMID:17636022 (120 citations)

14. Zhang DD. 2006. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38:769-789. PMID:17145701 (386 citations)

(Beginning of the independent position at University of Arizona)

 

13. Zhang DD, Lo SC, Sun Z, Habib GM, Lieberman MW, Hannink M. 2005. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem 280:30091-30099. PMID: 15983046. (141 citations)

12. Ansell PJ, Lo SC, Newton LG, Espinosa-Nicholas C, Zhang DD, Liu JH, Hannink M, Lubahn DB. 2005. Repression of cancer protective genes by 17beta-estradiol: ligand-dependent interaction between human Nrf2 and estrogen receptor alpha. Mol Cell Endocrinol 243:27-34. (40 citations)

11. Li X, Zhang DD, Hannink M, Beamer LJ. 2004. Crystal structure of the Kelch domain of human Keap1. J Biol Chem 279:54750-54758. (107 citations)

10. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. 2004. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24:10941-10953. PMID:15983046 (501 citations)

9.  Li X, Zhang DD, Hannink M, Beamer LJ. 2004. Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1. Acta Crystallogr D Biol Crystallogr 60:2346-2348. (13 citations)

8.  Zhang DD, Hannink M. 2003. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23:8137-8151. PMID: 14585973 (558 citations)

7.  Cullinan SB, Zhang DD, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. 2003. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198-7209. (447 citations)

6.  Salnikow K, Davidson T, Kluz T, Chen H, Zhou D, Costa M. 2003. GeneChip analysis of signaling pathways effected by nickel. J Environ Monit 5:206-209. (31 citations)

5.  Zhang DD, Hartsky MA, Warheit DB. 2002. Time course of quartz and TiO(2) particle-induced pulmonary inflammation and neutrophil apoptotic responses in rats. Exp Lung Res 28:641-670. (29 citations)

4.  Sachdev S, Bagchi S, Zhang DD, Mings AC, Hannink M. 2000. Nuclear import of IkappaBalpha is accomplished by a ran-independent transport pathway. Mol Cell Biol 20:1571-1582. (72 citations)

3. Salnikow K, Zhou D*, TKluz T, Wang C, and Costa M. 1999. A New Gene Induced by a Rise in Free Intracellular Ca2+ Following Ni 2+ Exposure. In Metals and Genetics. ed. Sarkar (Plenum, New York). 131-144.

2. Zhou D,Salnikow K, Costa M. 1998. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res 58:2182-2189. (266 citations)

1. Costa M, Salnikow K, Lee Y, Zhou D. 1997. Molecular biology of nickel carcinogenesis. J Inorg Biochem 67:372-372.

*Zhou D. is the former name of Donna D. Zhang

 

 

Publications

Former Graduate Students

Originally posted: September 9, 2013
Last updated: October 1, 2014
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