Serrine Lau, PhD
Director, Southwest Environmental Health Sciences Center
Director, Center for Toxicology
Pharmacology & Toxicology
Dr. Lau's research spans both basic research and translational research highlighted below:
(i) Mechanisms of chemical-induced nephrotoxicity and nephrocarcinogenicity: Dr. Lau is characterizing the molecular mechanisms of chemical-induced nephrocarcinogenesis in the Eker rat, which carries a mutation in the tuberous sclerosis (Tsc-2) tumor suppressor gene. The Tsc-2 tumor suppressor gene encodes the protein tuberin, a multi-functional protein with sequence homology to the GTPase activating protein for Rap1. Mutations in the Tsc-2 gene are associated with the development of renal tumors. Genetic and proteomic analysis of tumor tissue from the Eker rat model is being compared to human renal tumor tissue to determine the extent to which the animal model recapitulates the human disease.
(ii) Retinoid-mediated cytoprotection against reactive oxygen species (ROS)-induced tissue injury: Dr. Lau has demonstrated that All-trans retinoic acid (ATRA) provides cytoprotection against ROS-induced renal injury via mechanisms similar to ischemia preconditioning. Progressing from an in vitro cell model to an in vivo model of chemical- and ischemia/reperfusion-induced injury, the molecular and cellular mechanisms by which ATRA mediated cytoprotection are elucidated. This knowledge will provide insights into novel therapeutic strategies effective for clinical interventions during chemical- or hypoxia/ischemia-reperfusion injury.
(iii) Proteomics approaches for the identification of chemical-induced protein post-translational modifications: Proteins have long been appreciated as critical targets of environmental chemicals that produce adverse health effects. Recent developments in mass spectrometry ionization methods and instrumentation now make possible the rapid, high throughput analysis of proteins. The goals are to test two hypotheses: (1) topological, chemical, and physical features combine to determine which proteins are targets for chemical adduction, and (2) chemical-induced posttranslational modification of certain, critical proteins, causes a change in structure/function that contributes to the toxicological response to chemical exposure.
(i) Proteomics approaches for biomarker discovery for diseases such as diabetes, asthma and cancer:
(a) Environmental exposures, particularly at critical developmental windows in early life, can profoundly affect the phenotypes associated with complex diseases such as allergic asthma. Longitudinal population studies have consistently shown that early life, and possibly even prenatal exposure to certain domestic animals (e.g., indoor dogs) is associated with strong protection against asthma and asthma-related phenotypes (allergy, eczema) later in life. The overall goal of the project is to use proteomic methodologies to identify and characterize plasma proteomic signatures of early life dog exposure. This study will utilize samples and data from the Infant Immune Study (PIs Drs. Anne Wright and Marilyn Halonen), which enrolled at birth a large population of healthy children, and is still following them 8 years later, gathering detailed phenotypic information about immunological parameters, allergic sensitization and lung function. Funded by an ARRA grant Dr. Lau collaborates with Drs. Vercelli,Billheimer, and Halonen to study ”Proteomic signatures of an early life asthma-protective exposure.”
(b) Proteomic and Metabolomic Biomarker Investigation of Type 2 Diabetes (T2D): Dr. Lau initiated a collaborative project between investigators of UA-BIO5 and ASU-Biodesign. The team makes use of proteomics approaches to differentially profile the protein complements of healthy and diseased samples to identify novel biomarkers for diabetes. Progress has been made in examining glyco-oxidative stress and susceptibility to T2D complications. Studies focus on global qualitative and quantitative measurement of serum protein modifications by a reactive oxidative product of glucose, methylglyoxal in normal subjects and T2D patients.
(c) Mass Spectrometry (MS) Tissue Imaging and Global Protein Profiling: Since 2004 Dr. Lau has invested effort into the development of mass spectrometry-based tissue imaging. Results illustrate the application of matrix assisted laser desorption ionization MS-based tissue imaging to the discovery of stage-specific tumor markers. The development of mass spectrometry-based tissue imaging led to collaborations with investigators at Ventana/Roche; Bruker Daltonics Inc. and Arizona Cancer Center. The long-term strategy is to apply MS-imaging technologies to perform simultaneous detection/quantitation of drugs and drug-modulated protein profiles in frozen human tissues. This multiplexing approach can potentially provide molecular diagnosis and therapeutic intervention in cancer.
BS, University of Houston, 1974, Mathematics & Chemistry
PhD, University of Michigan, 1980, Pharmacology
(Selected from >150)
- Hattan, C.M., Shojaie, J., Lau, S.S. and Anders, M.W. Synthesis of 3-(1-Methyl-1H-imidazol-2-ylthio)propanoic acid and (E)-3-(1-Methyl-1H-imidazol-2-ylthio)acrylic acid, in press, 2011, Synth. Commun.
- Cohen, J.D., Gard, J.M.C., Nagle, R.B., Dietrich, J.D., Monks, T.J. and Lau, S.S. ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether induced Tuberous Sclerosis renal cell carcinoma. Toxicol. Sci., in press, 2011.
- Cohen, J.D., Tham, K., Mastrandrea, N.J., Gallegos, A.C., Monks, T.J. and Lau, S.S. cAMP-Dependent cytosolic mislocalization of p27kip-cyclin D1 during quinol-thioether induced Tuberous Sclerosis renal cell carcinoma, Toxicol. Sci. 122(2):361-371, 2011.
- Fisher, A.A., Labenski, M.T., Malladi, S., Chapman, J.D., Bratton, S.B., Monks, T.J. and Lau, S.S. The frequency of 1,4-benzoquinone-lysine adducts in cytochrome c correlate with defects in apoptosome activation, Toxicol. Sci. 122(1):64-72, 2011
- Felter, S.P., Conolly, R.B., Bercu, J.P., Bolger, P.M., Boobis, A.R., Bos, P.M.J., Carthew, P., Doerrer, N.G., Goodman, J.I., Harrouk, W.A., Kirkland, D.J., Lau, S.S., Llewellyn, G.C., Preston, R.J., Schoeny, R., Schnatter, A.R., Tritscher A., van Velsen, F. and Williams, G.M. A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens, Critical Reviews in Toxicology 41 (6): 507-544, 2011.
- Kimzey, M.J., Zarate, X., Galbraith, D.W. and Lau, S.S. Optimizing microarray-based in situ transcription-translation of proteins for matrix-assisted laser description ionization mass spectrometry, Anal. Biochem. 414: 282-286, 2011.
- Kimzey, M.J., Yassine, H.N., Riepel, B.M., Tsaprailis, G., Monks, T.J. and Lau, S.S. New Site(s) of Methylglyoxal-modified human serum albumin, identified by multiple reaction monitoring, alter warfarin binding and prostaglandin metabolism. Chemico-Biol Int. 192: 122-128, 2011.
- Zhang, F., Lau, S.S. and Monks, S.S. The cytoprotective effect of N-acetyl-L-cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis, Toxcol. Sci. 120: 87-97, 2011.
- Lau, S.S., Kuhlman, C., Shawn B. Bratton S.B. and Monks, T.J. Role of Hydroquinone-Thiol Conjugates in Benzene-Mediated Toxicity. Chemico-Biol Int., 184: 212-217, 2010.
- Monks, T.J., Butterworth, M., and Lau, S.S. The fate of Benzene Oxide. Chemico-Biol Int., 184:201-206, 2010.
- Fisher, A.A., Labenski, M.T., Monks, T.J., and Lau, S.S. Mass spectrometry-based methods to identify chemical modifications on proteins. I. Utilization of MALDI-TOF to determine chemical-protein adduct formation in vitro. In: Gautier, J.-C. (ed.). Drug Safety Evaluation Series - Methods of Molecular Medicine. Humana Press 2010; 303-16.
- Fisher, A.A., Labenski, M.T., Monks, T.J, and Lau, S.S. Mass spectrometry-based methods to identify chemical modifications on proteins: II. Utilization of LC-MS/MS analyses to identify site-specific chemical protein adducts in vitro. In: Gautier, J.-C. (ed.). Drug Safety Evaluation Series - Methods in Molecular Medicine. Humana Press 2010; 317-26.
- Labenski, M.T., Fisher, A.A., Monks, T.J., and Lau, S.S. Mass spectrometry-based methods to identify chemical modifications on proteins. III. One-dimensional western blotting coupled to LC-MS/MS analysis to identify chemical-adducted proteins in rat urine. In: Gautier, J.-C. (ed.). Drug Safety Evaluation Series - Methods of Molecular Medicine. Humana Press 2010; 327-38.
- Labenski, M.T., Fisher, A.A., Monks, T.J., and Lau, S.S. Mass spectrometry-based methods to identify chemical modifications on proteins. IV. Identification of chemical-adducted proteins in urine by multi-dimensional protein identification technology (LC/LC-MS/MS). In: Gautier, J.-C. (ed.). Drug Safety Evaluation Series - Methods of Molecular Medicine. Humana Press 2010; 339-50.
- Leinweber, B.D., Tsaprailis, G., Monks, T.J., and Lau, S.S. Improved MALDI-TOF imaging yields increased protein signals at high molecular mass. J. Am. Soc. for Mass Spectrometry, 20: 89-95, 2009.
- Labenski, M.T., Fisher, A.A., Lo, H.H., Monks, T.J. and Lau, S.S. Protein electrophile-binding motifs: lysine rich proteins are preferential targets of quinones. Drug Metab. and Disp., 37: 1211-1218, 2009.
- 18. Perfetti, X., O'Mathuna, B., Pizarro, N., Cuyas, E., Khymenets, O., Almeida, B., Pellegrini, M., Pichini, S., Monks, T.J., Lau, S.S., Farre, M., Pascual, J.A., Joglar, J., de La Torre, R. Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after Ecstasy ingestion. Drug Metab. and Disp, 37: 1448-1455, 2009.
- Erives, G.V., Lau, S.S., and Monks, T.J. Accumulation of neurotoxic thioether metabolites of 3,4-(±)-methylenedioxymethamphetamine in rat brain. J. Pharmacol. Exp. Ther., 324:284-292, 2008.
- Pizarro, N., de la Torre, R., Joglar, J., Okumura, N., Perfetti, X., Lau, S.S. and Monks, T.J. Serotonergic neurotoxic metabolites of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”): Synthesis isolation and characterization of diastereoisomers. Chem. Res. Toxicol., 21 (12) 2272-2279, 2008.
- Wozniak R.J., Klimecki, W.T., Lau, S.S., Feinstein, Y., Futscher, B.W. 5-aza-2'-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene 26:77-90, 2007.
- Fisher, A.A., Labenski, M.T., Gokhale, V., Bowen, M.E., Milleron, R.S., Bratton, S.B., Monks, T. J. and Lau, S.S. Quinone electrophiles selectively adduct “electrophile binding motifs” within cytochrome c. Biochemistry, 46:11090-11100, 2007.
- Yang M.Y., Lau S.S., and Monks T.J. 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential. Toxicol Sci. 2005 Jul; 86(1):92-100.
- National Research Council Committee on Human Health Risks of Trichloroethylene. Assessing Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: National Academies Press, 2006.
- Eblin, K.E., Bowen, M.E., Cromey, D., Bredfeldt, T.G., Mash, E.A., Lau, S.S. and Gandolfi, A.J. Arsenite and monomethylarsonous acid generate oxidative stress response in human bladder cell culture. Toxicol. Appl. Pharmacol. 217:7-14, 2006.
- Monks, T.J., Xie, R., Tikoo, K. and Lau, S.S. ROS-induced histone modifications and their role in cell survival and cell death. Drug Metab. Rev. 38:755-767, 2006.
- Monks, T.J. and Lau, S.S. Chemical-induced nephrocarcinogencity in the Eker rat: A model of chemical-induced renal carcinogenesis. In: Toxicology and the Kidney (L.H. Lash and J.B. Tarloff, Eds., CRC Press), p. 343-374, 2005.
- Person, M.D., Mason, D.E., Liebler, D.C., Monks, T.J. and Lau, S.S. Alkylation of cytochrome c by (glutathione-S-yl)-1,4-benzoquinone and iodoacetamide demonstrates compound- dependent site specificity. Chem. Res. Toxicol., 18:41-50, 2005.
- Jia, Z., Person, M.D., Dong, J., Shen, J, Hensley, S. C., Stevens , J.L., Monks, T.J. and Lau, S.S. GRP78 is essential for 11-deoxy, 16,16-dimethyl PGE2 mediated cytoprotection in renal epithelial cells. Am. J. Physiol. (Renal Physiol), 287: F1113-F1122, 2004. (Editorial Highlighted).
- Yoon, H.S., Ramachandiran, S., Chacko, M.A.S., Monks, T.J. and Lau, S. S. The tuberous sclerosis-2 tumor suppressor modulates ERK and B-raf activity in transformed renal epithelial cells. Am. J. Physiology, 286:F417-424, 2004.
- Patel, S.K., Ma, N., Monks, T.J. and Lau, S.S. Changes in gene expression during chemical-induced nephrocarcinogenicity in the Eker rat. Mol. Carcinogenesis, 38:141-154, 2003.
- Person, M.D., Lo, H.-H., Towndrow, K. M., Jia, Z., Monks, T. J. and Lau, S. S. Comparative identification of prostanoid inducible proteins by LC-ESI-MS/MS and MALDI-TOF mass spectrometry. Chem. Res. Toxicol. 16: 757-767, 2003.
- Person, M.D., Monks, T.J., and Lau, S.S. An integrated approach to identifying chemically induced posttranslational modifications using comparative MALDI-MS and targeted HPLC-ESI-MS/MS. Chem. Res, Toxicol. 16: 598-608, 2003.
- Habib, S.L., Phan, M.N., Patel, S.K., Li, D., Monks, T.J. and Lau, S.S. Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat. Carcinogenesis 24:573-582, 2003.
- Towndrow, K.M., Jia, Z., Lo, H.-H., Person, M. D., Monks, T. J. and Lau, S. S. 11-Deoxy, 16,16-dimethyl prostaglandin E2 induces specific proteins in association with its ability to protect against oxidative stress. Chem. Res. Toxicol. 16: 312-319, 2003.
- Yoon, H.S., Monks, T.J., Everitt, J.I., Walker, C.L. and Lau, S.S. Cell Proliferation is insufficient but loss of tuberin is necessary for chemical-induced nephrocarcinogenicity. Am. J. Physiology, 283: F262-F270, 2002.
- Yoon, H.S., Monks, T.J., Walker, C.L., and Lau, S.S. Transformation of kidney epithelial cells by a quinol-thioether via inactivation of the tuberous sclerosis-2 tumor suppressor gene. Mol. Cancinogenesis 31:37-45, 2001.
- Weber, T.J., Huang, Q., Monks, T.J., and Lau, S.S. Differential regulation of redox responsive transcription factors by the nephrocarcinogen 2,3,5-tris(glutathion-S-yl)hydroquinone. Chem. Res. Toxicol. 14:814-821, 2001.
- Lau, S.S., Monks, T. J., Everitt, J.I., Kleymenova, E., and Walker, C.L. Carcinogenicity of a nephrotoxic metabolite of the “nongenotoxic” carcinogen hydroquinone. Chem. Res. Toxicol. 14:25-33, 2001.
- Towndrow, K.T., Mertens, J.J.W., Jeong, J.K., Weber, T.J., Monks, T.J., and Lau, S.S. Stress- and growth-related gene expression are independent of chemical-induced prostaglandin E2 synthesis in renal epithelial cells. Chem. Res. Toxicol. 13:111-117, 2000.
- Kleiner, H.E., Rivera, M.I., Pumford, N.R., Monks, T.J., and Lau, S.S. Immunochemical detection of quinol-thioether derived protein adducts. Chem. Res. Toxicol. 11:1283-1290, 1998.
- Kleiner, H.E., Jones, T.W., Monks, T.J., and Lau, S.S. Immunochemical analysis of quinol-thioether derived covalent protein adducts in rodent species sensitive and resistant to quinol-thioether mediated nephrotoxicity. Chem. Res. Toxicol. 11:1291-1300, 1998.