Text Size: S | M | L            Format for printing

Directory

• All categories
• Students
• Faculty
• Staff
• Graduate Assistants/Associates

Serrine S Lau, PhD

Professor; Director, Southwest Environ Health Sci Ctr

Department:
Pharmacology and Toxicology

The focus of Dr. Lau's research involves coupling the metabolic activation of chemicals to their target organ toxicity. There are three major ongoing areas of research in Dr. Lau's laboratory:

1. Mechanism of hydroquinone mediated carcinogenicity: Specific goals include (a) investigation of the cellular and genetic basis for species differences in HQ-mediated nephrotoxicity and provision of a rational mechanistic basis for species extrapolations and human risk assessment and (b) determining the role of quinone-thioether metabolites of HQ in HQ-mediated nephrocarcinogenicity. 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. The Eker rat bears a mutation in one allele of the Tsc-2 gene, which predisposes these animals to renal cancer. We have initiated work to identify genetic risk factors responsible for susceptibility to spontaneous and carcinogen-induced tumors, utilizing the Eker rat as an animal model.

2. Prostanoid mediated cytoprotection: Prostaglandins (PGs) are potent signaling molecules that can exert both cellular and systemic effects. In particular, certain PGs protect cells against chemical-induced injury. This property has been termed cytoprotection. However, the mechanism(s) of PG-mediated cytoprotection remains unclear. In a model of chemical-induced toxicity, my laboratory has shown that treatment of a renal proximal tubule epithelial cell line (LLC-PK1) with toxicants increase the synthesis of PGE2 and that PGE2 is cytoprotective in a receptor-mediated process. Because PGE2 and 11-deoxy-16, 16-dimethyl-PGE2 (DDM-PGE2) activate AP-1/TRE DNA binding we hypothesize that induction of detoxifying enzymes may play a role in DDM-PGE2-mediated cytoprotection against chemical induced-cell injury. Utilizing HPLC-electrospray ionization mass spectrometric (ESI-MS/MS) and matrix-assisted laser desorption ionization time-of-flight mass spectrometric (MALDI-TOF-MS), we identified the potential cytoprotective proteins which involve in cytoskeletal organization and/or stimulation of an endoplasmic reticulum stress response. The functional significance of the cytoprotective proteins is currently under investigation. These studies provide insights into potential downstream targets of PG signaling.

3. Mass spectrometric approaches to proteomics. Proteins have long been appreciated as critical targets of environmental chemicals that produce toxicity and cancer. For many years, however, identifying protein targets of reactive chemical intermediates has been a nearly impossible task. Recent developments in mass spectrometry ionization methods and instrumentation now make possible the rapid, high throughput analysis of proteins. These analytical capabilities have driven the growth of proteomics, the study of the protein complement of the genome. The long-term goal of our initiative in this area is to use mass spectrometry methods for proteomics to identify the protein targets of environmental chemicals. Microelectrospray HPLC-MS and MALDI-TOF methods will be adapted to selectively identify post-translational modifications of proteins under various experimental conditions. In addition, we will determine chemical adducted peptides derived from proteolysis of modified proteins and characterize the modification at the level of amino acid sequence. One example for the application of this state-of-the-art technology is to test the hypothesis that specific cellular patterns of toxicity are linked to covalent modification of specific protein targets. We are currently developing mass spectrometry methods for protein identification to establish unique characteristics of quinone-thioether peptide adducts.

BS, University of Houston, 1974, Mathematics & Chemistry
PhD, University of Michigan, 1980, Pharmacology

1. Huang, Q., Lau, S.S., and Monks, T.J. Induction of gadd153 mRNA by nutrient deprivation is overcome by glutamine. Biochem. J. 341:225-231, 1999.

2. Jeong, J.K., Wogan, G.N., Lau, S.S., and Monks, T.J. Quinol-glutathione conjugate induced mutation spectra in the supf gene replicated in human AD293 cells and bacterial MBL50 cells. Cancer Res. 59:3641-3645, 1999.

3. Bai, F., Lau, S.S., and Monks, T.J. Glutathione and N-Acetylcysteine conjugates of -methyldopamine produces serotonergic neurotoxicity: Possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem. Res. Toxicol 12:1150-1157, 1999.

4. Weber, T.J., Monks, T.J., and Lau, S.S. DDM-PGE2-mediated cytoprotection in renal epiethelial cells by a thromboxane A2 receptor coupled to NF-kB. Am. J. Physiology 278: F270-F278, 2000.

5. 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.

6. Bratton, S.B., Lau, S.S., and Monks, T.J. The Putative Benzene Metabolite, 2,3,5-tris-(glutathion-S-yl)hydroquinone, depletes glutathione, stimulates sphingomyelin turnover, and induces apoptosis in HL-60 cells.” Chem. Res. Toxicol. 13:550-556, 2000.

7. 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.

8. 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.

9. Yoon, H.S., Walker, C.L., Monks, T.J., and Lau, S.S. Transformation of kidney epithelial cells by quinol-thioethers via inactivation of the tuberous sclerosis-2 tumor suppressor gene. Mol. Cancinogenesis 31:37-45, 2001.

10. Tikoo, K., Lau, S.S., and Monks, T.J. Histone H3 phosphorylation is couple to reactive oxygen species-induced oncotic cell death in renal proximal tubular epithelial cells. Mol. Pharmacol. 60:394-402, 2001.

11. Bai, F., Lau, S.S., and Monks, T.J. The serotonergic neurotoxicity of 3,4-(±)-methylenedioxyamphetamine and 3,4-(±)-methylenedioxymetamphetamine (ecstasy) is potentiated by inhibition of-glutamyl transpeptidase. Chem. Res. Toxicol. 14:863-870, 2001.

12. Li, D., Zhang, W., Zhu, J., Chang, P., Sahin, A., Singletary, E., Bondy, M., Hazra, T., Mitra, S., Lau, S.S., Shen. J. and DiGiovanni, J. Oxidative DNA damage and 8-hydroxy-2-deoxyguanosine DNA glycosylase/apurinic lyase in human breast cancer. Mol. Carcinogenesis 31:214-223, 2001.

13. Lau, S.S., Yoon, H.S., Patel, S.K., Everitt, J.I., Walker, C.L., and Monks, T.J. Mutagenicity and carcinogenicity of biological reactive intermediate’s derived from a "non-genotoxic" carcinogen. Adv. Exp. Med. Biol. 500:83-92, 2001.

14. Monks, T.J., Bai, F., Miller, R.T. and Lau, S.S. Serotonergic neurotoxicity of methylenedioxyamphetamine and methylenedioxymetamphetamine. Adv. Exp. Med. Biol. 500:397-406, 2001.

15. Li, D., Firozi, P. F., Zhang, W., Shen, J., DiGiovanni, J., Lau, S., Evans, D., Friess, H., Hassan, M., and Abbruzzese, J.L. DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mut. Res. 513:37-48, 2002.

16. 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 in the Eker rat. Am. J. Physiology, 283: F262-F270, 2002.

17. Ramachandiran, S., Huang, Q., Lau, S.S., Monks, T.J. Mitogen activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells. Chem. Res, Toxicol., 15: 1635-1642, 2002.

18. 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.

19. Liu, J.-W., Shen, J., Tanzillo-Swarts, A., Bhatia, B., Maldonado, C.M., Person, M.D., Lau, S.S. and Tang, D.G. Reduced or lost expression of annexins I and II in prostate cancer cells. Oncogene, 22:1475-1485, 2003.

20. 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.

21. 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.

22. Person, M.D., Lo, H.-H., Towndrow, K. M., Jia, Z., Monks, T. J. and Lau, S. S. Comparative identification of proteins by LC-ESI-MS/MS and MALDI-TOF mass spectrometry. Chem. Res. Toxicol. 16: 757-767, 2003.

23. 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.

24. Yoon, H.S., Ramachandiran, 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.

25. Monks, T.J., Jones, D.C., Bai, F., and Lau, S.S. The role of metabolism in 3,4-(±)-methylenedioxyamphetamine and 3,4-(±)-methylenedioxymethamphetamine (ecstasy) neurotoxicity. Ther. Drug Monitoring, 26(2), 132-136, 2004.

26. Jones, D.C., Lau, S.S., and Monks, T.J. Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells. J. Pharmacol Exp. Ther., 311, 298-306, 2004.

27. Soliman, A.S., Vulimiri, S.V., Kleiner, H.E., Shen, J., Eissa, S., Morad, M., Taha, H., Lukmanji, F., Li, D., Johnston, D. A., Lo, H. H., Lau, S.S., DiGiovanni, J. and Bondy, M. L. High levels of oxidative DNA damage in lymphocyte DNA of premenopausal breast cancer patients from Egypt. Int. J. Environ. Health Res. 14: 121-134, 2004.

28. Dong, J., Everitt, J.I., Lau, S.S. and Monks, T.J. Induction of ERK1/2 and Histone H3 phosphorylation within the outer stripe of the outer medulla of the Eker Rat by 2,3,5-tris-(glutathion-S-yl)hydroquinone. Toxicol. Sci. 80: 350-357, 2004.

29. Dong, J., Ramachandiran, S., Tikoo, K., Jia, Z., Lau, S.S., and Monks, T.J. EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 is required for ROS-induced renal cell death. Am. J. Physiol. (Renal Physiol), 287: F1049-F1058, 2004.

30. 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 prostaglandin E2 mediated cytoprotection in renal epithelial cells. Am. J. Physiol. (Renal Physiol), 287: F1113-F1122, 2004. (Editorial Highlighted).

31. Abel, E.L., Lyon, R.P., Bammler, T.K., Lau, S.S., Monks, T.J. and Eaton, D.L. Investigation of endogenous estradiol metabolites as isoform-specific inhibitors of human glutathione S. transferases. Chem. Biol. Inter., 151, 21-32, 2004.

32. 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.

33. 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.

34. Jones, D.C., Duvauchelle, C., Ikegami, A., Olsen, C.M., Lau, S.S. de la Torre, R. and Monks T.J. Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain. J. Pharmacol Exp. Ther., 313:422-431, 2005.