Serrine Lau, PhD

Professor
Pharmacology and Toxicology
Director
Southwest Environmental Health Sciences Center
Director
Center for Toxicology
Department(s): 
Pharmacology & Toxicology

lau@pharmacy.arizona.edu
520-626-0460 520-626-2823
FAX: 520-626-6944
Pharmacy (Skaggs) Building 331B

Dr. Lau's research spans both basic research and translational research highlighted below:

Basic Research:

(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) Signaling pathways underlying renal and prostate cancer where elevated cyclin D1 is observed:

(a)Renal cancer: Investigation of the mechanisms by which pentoxifylline (PTX) decreases cyclin D1 and arresting renal cancer cells in the G1 phase. Our current work involves the identification of genetic risk factors responsible for susceptibility to spontaneous and carcinogen-induced tumors, utilizing the Eker rat as an animal model. Cyclin D1 is required for cells to progress from the G1 phase into the S phase of the cell cycle. Several tumors display elevations in cyclin D1, concomitant with increased cell cycle progression and proliferation. QTRRE (rodent) and ACHN (human) cell models of renal cell carcinoma display elevated cyclin D1 protein levels. PTX a competitive non-specific phosphodiesterase inhibitor, has found recent use as an adjunct in chemotherapy for patients to help treat cachexia and capillary leak syndrome. We now show that PTX decreases cyclin D1 protein levels by inhibiting protein translation, which promotes G1 phase cell cycle arrest. Our findings reveal a novel anti-cancer chemotherapeutic property of PTX, the utility of PTX as an adjuvant therapy in the treatment of cancer will be further explored.

(b) Prostate cancer: Environmental exposure to carcinogens causes loss of tumor suppressor genes. Phosphatase and tensin homolog (PTEN) negatively regulates the AKT pathway, and the PTEN gene is mutated/deleted in ~70% of prostate cancer cases. Downstream of AKT, eukaryotic initiation factor 4E binding protein 1 (4EBP1) regulates cyclin D1 translationally. In contrast, ERK, a member of the mitogen activated protein kinase (MAPK) pathway, regulates cyclin D1 transcriptionally. Both the AKT and MAPK signaling pathways contribute to disease progression in prostate cancer. A PTEN-deficient human prostate cancer cell line, LNCaP, and a PTEN-positive human prostate cancer cell line, DU145, were used to examine the role of PTEN status in determining drug sensitivity to Amuvatinib, a receptor tyrosine kinase inhibitor, and Erlotinib, an epidermal growth factor inhibitor. 1D and 2D Western blot analysis revealed that combination drug treatment of LNCaP cells caused a decrease in 4EBP1 pSer65, pThr70 and pThr37/46, with a concomitant decrease in cyclin D1 protein. Such combination treatment, however, did not modulate pERK status. Moreover, single drug treatment with Amuvatinib, but not Erlotinib, decreased p-4EBP1 and cyclin D1 protein levels. In DU-145 cells, combination drug treatment had no effect on p-4EBP1 status, but decreased p-ERK and cyclin D1 protein levels. Additionally, single drug treatment with Erlotinib, but not Amuvatinib, caused a loss of p-ERK and cyclin D1. The data reveal the differential modulation of cyclin D1, and its upstream regulators, in the PTEN- and PTEN+ cell lines by Amuvatinib and Erlotinib. Such differential responses likely contribute to specific anti-tumor agent efficacy. An appreciation of factors that determine the cell-dependent modulation of cyclin D1 will assist in the selection of appropriate biomarkers to assist in directing patient-targeted therapy.

(iii) 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.

(iv) Proteomics approaches for the identification of chemical-induced protein post-translational modifications in association with nephrotoxicity and hematotoxicity:

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.

Translational Research:

(i) Proteomics approaches for biomarker discovery for diseases such as diabetes, asthma and cancer:

(a) Early-life asthma-protection: 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. Moreover the T2DM first-line drug metformin (MF) significantly reduces diabetes-related endpoints and mortality more effectively than other glucose-lowering medications. We have examined whether, in addition to its ability to reduce hepatic gluconeogenesis, MF directly scavenges dicarbonyls as an additional mechanism to reduce T2DM complications.

(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.

Education: 

BS, University of Houston, 1974, Mathematics & Chemistry

PhD, University of Michigan, 1980, Pharmacology

Publications

Lizarraga LL, Cholanians AB, Phan AV, Herndon JM, Lau SS, Monks TJ (2014) Vesicular Monoamine Transporter 2 and the Acute and Long-Term Response to 3,4-(6)-Methylenedioxymethamphetamine. Toxicol Sci. 143(1):209-19. PMID:25370842; PMCID: 4274386. (doi:10.1093/toxsci/kfu222).

Lizarraga LE, Cholanians AB, Phan AV, Herndon JM, Lau SS, Monks TJ (2014) Vesicular Monoamine Transporter 2 and the Acute and Long-Term Response to 3,4-(±)-Methylenedioxymethamphetamine. Toxicol. Sci. 143;209-218.

Yassine HN, Jackson AM, Reaven PD, Nedelkov D, Nelson RW, Lau SS, Borchers CH (2014) The Application of Multiple Reaction Monitoring to Assess Apo A-I Methionine Oxidations in Diabetes and Cardiovascular Disease. J. Translational Proteomics 4:18-24. PMID: 25705587; PMCID: 4331021

Yassine HN, Belopolskaya A, Schall C, Stump CS, Lau SS, Reaven PD (2014) Enhanced cholesterol efflux to HDL through the ABCA1 transporter in hypertriglyceridemia of type 2 diabetes. Metabolism 63(5):727-734. PMID: 24636347; PMCID 4014062 (doi: 10.1016/j.metabol.2014.03.001)

Lizarraga LE, Phan AV, Cholanians AB, Herndon JM, Lau SS, Monks TJ (2014) Serotonin reuptake transporter (SERT) deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymethamphetamine, and attenuates depletions in serotonin levels in Sert-KO rats. Toxicol Sci, 139(2): 421-431. PMID: 24595820; PMCID: 4031621. (doi: 10.1093/toxsci/kfu039).

Brown JM, Kuhlman C, Terneus MV, Labenski MT, Lamyaithong AB, Ball JG, Lau SS, Valentovic MA (2014) S-Adenosyl-L-Methionine Protection of Acetaminophen Mediated Oxidative Stress and  Identification of  Hepatic 4-Hydroxynonenal Protein Adducts by Mass Spectrometry. Appl. Pharm. Toxicol. 281:174-184. PMID: 25246065; PMCID 4418180. (doi: 10.1016/j.taap.2014.08.027).

Brown JM, Kuhlman C, Terneus MV, Labenski MT, Lamyaithong AB, Ball JG, Lau SS, Valentovic MA (2014) S-Adenosyl-L-Methionine Protection of  Acetaminophen Mediated Oxidative Stress and  Identification of  Hepatic 4-Hydroxynonenal Protein Adducts by Mass Spectrometry. Appl. Pharm. Toxicol. 281:174-184. PMID: 25246065; NIHMS in process. (doi: 10.1016/j.taap.2014.08.027).

Yassine HN, Jackson AM, Borges CR, Billheimer D, Koh H, Smith D, Reaven P, Lau SS, Borchers CH (2014) The application of multiple reaction monitoring and multi-analyte profiling to HDL proteins. Journal of Lipids in Health and Disease, 13:8-18. PMID: 24397693; PMCID: 3900256. (doi: 10.1186/1476-511X-13-8).

Herndon JM, Cholanians AB, Lizarraga LE, Lau SS, Monks TJ (2014) Catechol O-methyltransferase and 3,4-(±)methylenedioxy-methamphetamine toxicity. Toxicol. Sci, 139(1):162-73. PMID: 24591155; PMCID: 4007109. (doi: 10.1093/toxsci/kfu035)

Herndon JM, Cholanians AB, Lau SS, Monks TJ (2014) Glial cell response to 3,4-(±)-methylenedioxymethamphetamine and its metabolites. Toxicol Sci, 138:130-138. PMID: 24299738; PMCID: 3930364 (doi: 10.1093/toxsci/kft275).

Yassine H, Borges CR, Schaab MR, Billheimer D, Stump C, Reaven P, Lau SS, Nelson R (2013) Mass spectrometric immunoassay and MRM as targeted MS-based quantitative approaches in biomarker development: Potential applications to cardiovascular disease and diabetes. Proteomics Clin. Appl., 7: 528–540. PMID: 23696124; PMCID: 4029342 (doi: 10.1002/prca.201200028).

Monks TJ, Lau SS (2013) Reactive Intermediates: Molecular and MS-based approaches to assess the functional significance of chemical-protein adducts. Toxicol. Pathol., 41(2):315-321. PMID 23222993; PMCID: 4007760 (doi: 10.1177/0192623312467399).

Flores RJ, Li Y, Yu A, Shen J, Lau SS, Vannucci M, Lau CC, Man T-K (2012) A Systems biology approach reveals common metastatic pathways in osteosarcoma. BMC Systems Biology Journal, 6:50. PMID: 22640921; PMCID: 3431263 (doi:10.1186/1752-0509-6-50). 

Zhang F, Lau SS, Monks TJ (2012) A Dual role for poly(ADP-ribose)polymerase-1 (PARP-1) during caspase-dependent apoptosis. Toxicol. Sci., 128(1):103-114. PMID: 22523229; PMCID: 3491962. (doi: 10.1093/toxsci/kfs142)

Yassine H, Kimzey MJ, Galligan MA, Gandolfi AJ, Stump CS, Lau SS (2012) Adjusting for urinary creatinine overestimates arsenic concentrations in diabetics. CardioRenal Medicine 2: 26-32. PMID: 22493600; PMCID: 3318926 (doi: 10.1159/000334225).

Cohen JD, Gard JMC, Nagle RB, Dietrich JD, Monks TJ, Lau SS (2011) ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether induced Tuberous Sclerosis renal cell carcinoma. Toxicol. Sci., 124 (1): 75-87. PMID: 21813464; PMCID: 3196650 (doi:10.1093/toxsci/kfr203).

Cohen JD, Gard JMC, Nagle RB, Dietrich JD, Monks TJ, Lau SS (2011) ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether induced Tuberous Sclerosis renal cell carcinoma. Toxicol. Sci., 124 (1): 75-87. PMID: 21813464; PMCID: 3196650 (doi:10.1093/toxsci/kfr203).

Cohen JD, Tham K, Mastrandrea NJ, Gallegos AC, Monks TJ, Lau SS (2011) cAMP-Dependent cytosolic mislocalization of p27kip-cyclin D1 during quinol-thioether induced Tuberous Sclerosis renal cell carcinoma. Toxicol. Sci. 122(2): 361-371. PMID: 21693435; PMCID: 3155088. (doi:10.1093/toxsci/kfr118).

Kimzey MJ, Zarate X, Galbraith DW, Lau SS (2011) Optimizing microarray-based in situ transcription-translation of proteins for matrix-assisted laser desorption ionization mass spectrometry. Anal. Biochem. 414: 282-286. PMID: 21477576; PMCID:4120701 (doi:10.1016/j.ab.2011.03.030).

Fisher AA, Labenski MT, Malladi S, Chapman JD, Bratton SB, Monks TJ, Lau SS (2011) The frequency of 1,4-benzoquinone-lysine adducts in cytochrome c correlate with defects in apoptosome activation. Toxicol. Sci. 122(1):64-72. PMID: 21527774; PMCID: 3203403 (doi:10.1093/toxsci/ kfr085).

Felter SP, Conolly RB, Bercu JP, Bolger PM, Boobis AR, Bos PMJ, Carthew P, Doerrer NG, Goodman JI, Harrouk WA, Kirkland DJ, Lau SS, Llewellyn GC, Preston RJ, Schoeny R, Schnatter AR, Tritscher A, van Velsen F, Williams GM (2011) A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens. Critical Reviews in Toxicology 41(6): 507–544. PMID: 21591905 (doi: 10.3109/10408444.2011.552063). N/A for PMC

Zhang F, Lau SS, Monks TJ (2011) 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. (Editorial Highlighted). PMID: 21135414; PMCID: 3044202 (doi:10.1093/toxsci/kfq364).

Kimzey MJ, Yassine HN, Riepel BM, Tsaprailis G, Monks TJ, Lau SS (2011) 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. PMID: 20934417; PMCID: 3050118 (doi:10.1016/j.cbi.2010.09.032).

Labenski MT, Fisher AA, Monks TJ, Lau SS (2011) 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; Methods Mol Biol, 691: 339-350. PMID: 20972764; PMCID: 4083842 (doi: 10.1007/978-1-60761-849-2_21).

Labenski MT, Fisher AA, Monks TJ, Lau SS (2011) 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; Methods Mol Biol, 691:327-338. PMID: 20972763; PMCID: 4096012 (doi: 10.1007/978-1-60761-849-2_20).

Fisher AA, Labenski MT, Monks TJ, Lau SS (2011) 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; Methods Mol Biol, 691: 317-326. PMID: 20972762; PMCID:4120700 (doi: 10.1007/978-1-60761-849-2_19).

Fisher AA, Labenski MT, Monks TJ, Lau SS (2011) 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; Methods Mol Biol, 691:303-316. PMID: 20972761 PMCID: 4096023 (doi: 10.1007/978-1-60761-849-2_18).

Monks TJ, Butterworth M, Lau SS (2010) The fate of Benzene Oxide. Chemico-Biol Int, 184:201-206.  PMID: 20036650; PMCID: 4096023 (doi: 10.1016/j.cbi.2009.12.02).

Lau SS, Kuhlman C, Bratton SB, Monks TJ (2010) Role of Hydroquinone-Thiol Conjugates in Benzene-Mediated Toxicity. Chemico-Biol Int. 184: 212-217. PMID: 20034486; PMCID: 2846198 (doi:10.1016/j.cbi.2009.12.016).

Ricardo J. Flores RJ, Li, Y., Yu, A., Jianhe Shen, J., Lau SS, Vannucci, M., Lau CC, and Man, T-K (2012) A Systems biology approach reveals common metastic pathways in osteosarcoma. BMC Systems Biology Journal, 6:50. PMID: 22640921; PMCID: 3431263 (doi: 10.1186/1752-0509-6-50).

Person MD, Mason DE, Liebler DC, Monks TJ, Lau SS (2005) Alkylation of cytochrome c by (glutathione-S-yl)-1,4-benzoquinone and iodacetamide demonstrates compound- dependent site specificity. Chem Res Toxicol, 18: 41-50. PMID: 15651848 (doi: 10.1021/tx049873n). 

Monks TJ, Lau SS (2005) Chemical-induced nephrocarcinogencity in the Eker rate: A model of chemical-induced renal carcinogenesis. Toxicology and the Kidney (L.H. Lash and J.B. Tarloff, Eds, CRC Press), p. 343-374. 

Jones DC, Duvauchelle C, Ikegami A, Olsen CM, Lau SS, Torre R, Monks TJ (2005) Serotonergic Neurotoxic Metabolites of Ecstasy Identitfied in Rat Brain. J Pharmacol Exp Ther, 313:422-431. PMID:15634943 (doi: 10.1124/jpet.104.0776 28).

Yang MY, Lau SS, Monks TJ (2005) 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHG)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absense of a decrease in the mitochondrial membrane potential. Toxicol Sci, 86(1):92-100. PMIDL 15800030 (doi:10.1093/toxsci/kfi 165). 

National Research Council Committe on Human Health Risks of Trichloroethylene, Assessing Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: National Academies Press, 2006.

Eblin KE, Bowen ME, Cromey D, Bredfeldt TG, Mash EA, Lau SS, Gandolfi AJ (2006) Aresenite and monomethylarsonous acid generate oxidative stress response in human bladder cell culture. Toxicol Appl Pharmacol, 217:7-14. PMID 16930658. (doi:10.1016/j.tapp.2006.07.004). 

Monks TJ, Xie R, Tikoo K, Lau SS (2006) ROS-induced histone modifications and their role in cell survival and cell death. Drug Metab Rev, 38:755-767. PMID:17145700 (doi:10.1080/03602530600959649). 

Wozniak RJ, Klimecki WT, Lau SS, Feinstein Y, Futscher BW (2007) 5-aza-2'deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivaton. Oncogene, 26:77-90. PMID: 16799634 (doi:10.1038/sj.onc.1209763). 

Fisher AA, Labenski MT, Gokhale V, Bown ME, Milleron RS, Bratton SB, Monks TJ, Lau SS (2007) Quinone electrophiles selectively adduct electrophile binding motifs within cytochrome c. Biochemisty, 46:11090-11100. PMIDL 17824617 (doi:10.1021/bi700613w). 

Erives GV, Lau SS, Monks TJ (2008) Accumulation of neurotoxic thioether metabolites of 3,4-(±)-methylenedioxymethamphetamine in rat brain. J Pharmacol Exp Ther, 324:284-292. PMID: 17906065 (doi:10.1124/jpet.107.128785). 

Pizarro N, Torre R, Joglar J, Okumura N, Perfetti X, Lau SS, Monks TJ (2008) Serotonergic neurotoxic metabolites of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy): Synthesis, isolation, and characterization of diastereoisomers. Chem Res Toxicol, 21(12):2272-2279. PMID: 19548351; PMCID: 4075178 (doi:10.1021/tx8002017). 

Leinweber BD, Tsaprailis G, Monks TJ, Lau SS (2009) Improved MALDI-TOF imaging yields increased protein signals at high molecular mass. J Am Soc for Mass Spectrometry, 20:89-95. PMID: 18926723; PMCID: 2671225. (doi: 10.1016/j.jasms.2008.09.008).

Labenski MT, Fisher AA, Lo HH, Monks TJ, Lau SS (2009) Protein electrophile-binding motifs: lysine rich proteins are preferential targets of quinones. Drug Metab and Disp, 37:1211-1218. PMID: 19251821; PMCID: 2683689 (doi:101.1124/dmd.108.026211). 

Perfetti X, O'Mathuna B, Pizarro N, Cuyas E, Khymenets O, Almeida B, Pellegrini M, Pichini S, Monks TJ, Lau SS, Farre M, Pascual JA, Joglar J, Torre R (2009) Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after Ecstasy ingestion. Drug Metab And Disp, 37:1448-1455. PMID: 19349378; PMCID: 2698942 (doi: 10.1124/dmd.108.026393). 

Publications
Originally posted: September 9, 2013
Last updated: May 8, 2015
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