Serrine Lau, PhD
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) 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.
(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.
BS, University of Houston, 1974, Mathematics & Chemistry
PhD, University of Michigan, 1980, Pharmacology
Lizarraga, L.E., Cholanians, A.B., Phan, A.V., Herndon, J.M., Lau, S.S. and Monks, T.J. Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine. Toxicol Sci, 143:209-218, 2014. PMID:25370842; PMCID: 4274386
Yassine, H.N., Jackson, A.M., Reaven, P.D., Nedelkov, D., Nelson, R.W., Lau, S.S. and Borchers, C.H. The Application of multiple reaction monitoring to assess apo A-I methionine oxidations in diabetes and cardiovascular disease. J Translational Proteomics, 4:18-24, 2014. PMID: 25705587; PMCID: 4331021
Yassine, H.N., Belopolskaya, A., Schall, C., Stump, C.S., Lau, S.S. and Reaven, P.D., Enhanced cholesterol efflux to HDL through the ABCA1 transporter in hypertriglyceridemia of type 2 diabetes. Metabolism, 63(5):727-734, 2014. PMID: 24636347; PMCID: 4014062
Lizarraga, L.E., Phan, A.V., Cholanians, A.B., Herndon, J.M., Lau, S.S. and Monks, T.J. Serotonin reuptake transporter (SERT) deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymeth-amphetamine, and attenuates depletions in serotonin levels in Sert-KO rats. Toxicol Sci, 139(2): 421-431, 2014. PMID: 24595820; PMCID: 4031621
Zhang F., Xie, R., Munoz F., Lau S.S. and Monks T.J. PARP-1 Hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death. Toxicol Sci, 140(1):118-134, 2014. PMID: 24752504; PMCID: 4081636
Yassine, H.N., Jackson, A.M., Borges, C.R., Billheimer, D., Koh, H., Smith, D., Reaven, P., Lau, S.S. and Borchers, C.H. The application of multiple reaction monitoring and multi-analyte profiling to HDL proteins. Journal of Lipids in Health and Disease, 13:8-18, 2014. PMID: 24397693; PMCID: 3900256
Herndon, J.M.,Cholanians, A.B, Lizarraga, L.E., Lau, S.S., and Monks, T.J. Catechol O-methyltransferase and 3,4-(±)methylenedioxy-methamphetamine toxicity. Toxicol Sci, 139(1):162-73, 2014. PMID: 24591155; PMCID: 4007109
Herndon, J.M., Cholanians, A.B, Lau, S.S., and Monks, T.J. Glial cell response to 3,4-(±)-methylenedioxymethamphetamine and its metabolites. Toxicol Sci, 138:130-138, 2014. PMID: 24299738; PMCID: 3930364
Yassine, H., Borges, C.R., Schaab, M.R., Billheimer, D., Stump, C., Reaven, P., Lau, S.S., and Nelson, R. 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, 2013. PMID: 23696124; PMCID: 4029342
Monks, T.J. and Lau, S.S. Reactive Intermediates: Molecular and MS-based approaches to assess the functional significance of chemical-protein adducts. Toxicol Pathol, 41(2):315-321, 2013. PMID: 23222993; PMCID: 4007760
Ricardo J. Flores, R.J., Li, Y., Yu, A., Jianhe Shen, J., Lau, S.S., Vannucci, M., Lau, C.C., and Man, T-K. A Systems biology approach reveals common metastatic pathways in osteosarcoma. BMC Systems Biology Journal, 6:50, 2012. PMID: 22640921; PMCID: 3431263 Highly Accessed, categorized by BioMed Central, July 23, 2012; published on May 28, 2012 and total accesses on November 29, 2012 are 1453
Zhang, F., Lau, S.S and Monks, T. J. A Dual role for poly (ADP-ribose) polymerase-1 (PARP-1) during caspase-dependent apoptosis. Toxicol Sci, 128(1):103-114, 2012. PMID: 22523229; PMCID: 3491962
Yassine, H., Kimzey, M.J., Galligan, M. A., Gandolfi, A.J., Stump, C.S. and Lau, S.S. Adjusting for urinary creatinine overestimates arsenic concentrations in diabetics. CardioRenal Medicine 2: 26-32, 2012. PMID: 22493600; PMCID: 3318926
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, 124 (1): 75-87, 2011. PMID: 21813464; PMCID: 3196650
Wnek, S.M., Kuhlman, C.L., Camarillo, J. M., Medeiros, M.K., Liu, K.J., Lau, S.S. and Gandolfi, A.J. Interdependent genotoxic mechanisms of monomethylarsonous acid: Role of ROS-induced DNA damage and poly (ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells. Toxicol Appl Pharm, 257: 1-13, 2011. PMID: 21925530; PMCID: 3220758
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. PMID: 21693435; PMCID: 3155088
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 desorption ionization mass spectrometry. Anal Biochem, 414: 282-286, 2011. PMID: 21477576; PMCID: 4120701
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. PMID: 21527774; PMCID: 3203403
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. PMID: 21591905
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 Inter, 192: 122-128, 2011. PMID: 20934417; PMCID: 3050118
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 2011; Methods Mol Biol, 691: 339-350. PMID: 20972764; PMCID: 4083842
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 2011; Methods Mol Biol, 691:327-338. PMID: 20972763; PMCID: 4096012
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 2011; Methods Mol Biol, 691: 317-326. PMID: 20972762; PMCID: 4120700
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 2011; Methods Mol Biol, 691:303-316. PMID: 20972761; PMCID: 4096023
Monks, T.J., Butterworth, M., and Lau, S.S. The fate of benzene oxide. Chemico-Biol Inter, 184:201-206, 2010. PMID: 20036650; PMCID: 4414400
Lau, S.S., Kuhlman, C., Bratton S.B. and Monks, T.J. Role of hydroquinone-thiol conjugates in benzene-mediated toxicity. Chemico-Biol Inter, 184: 212-217, 2010. PMID: 20034486; PMCID: 2846198