The University of Texas at Arlington

                    Sharad S. Singhal

Phone:
(817) 272-5444

FAX:
 (817) 272-3808

E-Mail:
ssinghal@uta.edu

B.Sc., Agra University, India (1982)

M.Sc., Agra University, India (1984)

Ph.D., Central Drug Research Institute, Lucknow, India (1989)

Postdoctoral Fellow: University of Texas Medical Branch, Galveston, Texas (1989- 1993)

Protein chemistry, enzymology, expression and regulation of glutathione S-transferases and their structural and functional interrelationships, and in the field of chemotherapy drug resistance, particularly in the mechanisms involved in mediating drug resistance to a commonly used important chemotherapy drug, adriamycin (doxorubicin).

Isolation of erythrocyte membrane protein with ATPase activity stimulated by a number of chemotherapy agents including doxorubicin, mitoxantrone, vincristine, vinblastine, and mitomycin C as well as glutathione conjugates of a number of electrophilic xenobiotics. Isolation and characterization of membrane transporters immunologically related to DNP-SG ATPase in membrane fractions of human cancer cell lines and determine to mediate ATP-dependent primary active transport of GS-E as well as chemotherapy drugs.

Representative Publications:

Ramesh, V., Singh, C. and Singhal, S.S. (1987) Isoelectric point determination of immobilized enzymes employing polyanionic and polycationic enzyme inhibitors as tools.  Appl. Biochem. Biotech. 16:191-199.

Singhal, S.S., Gupta, S., Ahmad, H., Sharma, R., and Awasthi, Y.C. (1990) Characterization of a novel α-class anionic glutathione S-transferase isoenzyme from human liver. Arch. Biochem. Biophys. 279:45-53.

Singhal, S.S., Sharma, R., Gupta, S., Ahmad, H., Zimniak, P., Radominska, A., Lester, R., and Awasthi, Y.C. (1991) The anionic conjugates of bilirubin and bile acids stimulate ATP hydrolysis by S-(dinitro-phenyl) glutathione ATPase of human erythrocyte.  FEBS Lett. 281:255-257.

Singhal, S.S., Saxena, M., Ahmad, H., Awasthi, S., Haque, A.K., and Awasthi, Y.C. (1992) Glutathione S-transferases of human lung:  characterization and evaluation of the protective role of the α-class isozymes against lipid peroxidation. Arch. Biochem. Biophys. 299:232-241.

Zimniak, P., Singhal S.S., Srivastava, S.K., Awasthi, S., Sharma, R., Hayden, J.B., and Awasthi, Y.C. (1994) Estimation of genomic complexity, heterologous expression and enzymatic characterization of mouse glutathione S-transferase mGSTA4-4 (GST 5.7). J. Biol. Chem., 269:992-1000. 

Singhal, S.S., Zimniak, P., Sharma, R., Srivastava, S.K., Awasthi, S., and Awasthi, Y.C. (1994) A novel glutathione S-transferase isozyme similar to GST 8-8 of rat and mGSTA4-4 (GST 5.7) of mouse is selectively expressed in human tissues. Biochim. Biophys. Acta 1204:279-286. 

Awasthi, S., Singhal, S.S., Srivastava, S.K., Zimniak, P., Bajpai, K.K., Saxena, M., Sharma, R., Ziller, S.A.III, Frenkel, E., Singh, S.V., He, N.G., and Awasthi, Y.C. (1994) ATP-dependent transport of doxorubicin, daunomycin and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein.  J. Clin. Invest. 93:958-965.

Awasthi, S., Singhal, S.S., Srivastava, S.K., Torman, R.T., Zimniak, P., Bandorowicz-Pikula, J., Singh, S.V., Piper, J.T., Awasthi, Y.C., and Pikula, S. (1998) ATP-dependent human erythrocyte glutathione-conjugate transporter. I. Purification, photoaffinity labeling and kinetic characteristics of ATPase activity.  Biochemistry 37:5231-5238. 

Awasthi, S., Singhal, S.S., Pikula, S. Piper, J.T., Srivastava, S.K., Torman, R.T., Bandorowicz-Pikula, J., Lin, J.T., Singh, S.V., Zimniak, P., and Awasthi, Y.C. (1998) ATP-dependent human erythrocyte glutathione-conjugate transporter. II. Functional reconstitution of transport activity. Biochemistry 37:5239-5248.

Awasthi, S., Cheng, J., Singhal, S.S., Saini, M.K., Pandya, U., Pikula, S., Pikula, J., Singh, S.V., Zimniak, P., Awasthi, Y.C. (2000) Novel function of human RLIP76: ATP-dependent transport of glutathione-conjugates and doxorubicin. Biochemistry 39:9327-9334.

Awasthi, S., Cheng, J., Singhal, S.S., Sharma, R., Pandya, U., Singh, S.V., Zimniak, P. and Awasthi, Y.C. (2001). Functional reassembly of xenobiotic transport from the N-terminal and C-terminal domains of RLIP76 and identification of ATP binding sequences. Biochemistry 40:4159-4168.

Cheng, J., Sharma, R., Yang, Y., Singhal, S.S., Sharma, A., Saini, M.K., Singh, S.V., Zimniak, P., Awasthi, S., and Awasthi, Y.C. (2001) Accelerated metabolism and exclusion of 4-hydroxy-nonenal   through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. J. Biol. Chem. 276: 41213-41223.

Singhal, S.S., Singhal, J., Sharma, R., Singh, S.V., Zimniak, P., Awasthi, Y.C., and Awasthi, S. (2003) Role of RLIP76 in lung cancer doxorubicin resistance: The ATPase activity of RLIP76 correlates with doxorubicin and 4-Hydroxynonenal resistance in lung cancer cells. Int. J. Oncology 22:365-375.

Yang, Y., Sharma, A., Sharma, R., Patrick, B., Singhal, S. S., Zimniak, P., Awasthi, S. and Awasthi, Y. C. (2003) Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: Role of 4-hydroxynonenal in UVA mediated signaling for apoptosis. J. Biol. Chem. 278:41380-41388.

Sharma, R., Singhal, S.S., Wickramarachchi, D., Awasthi, Y.C., and Awasthi, S. (2004) RLIP76 (RALBP1) mediated transport of leukotrienes C4 (LTC4) in cancer cells: Implications in drug resistance. Int. J. Cancer 112: 934-942.

Yadav, S., Singhal, S.S., Singhal, J., Wickramarachchi, D., Knutson, E., Albrecht, T.B., Awasthi, Y.C. and Awasthi, S. (2004) Identification of Membrane Anchoring Domains of RLIP76 using Deletion Mutants Analyses. Biochemistry 43:16243-16253.

Stuckler, D., Singhal, J., Singhal, S.S., Yadav, S., Awasthi, Y.C. and Awasthi, S. (2005) RLIP76 Transports Vinorelbine and Mediates Drug Resistance in Non-Small Cell Lung Cancer. Cancer Res. 65:991-998.

Singhal, S.S., Yadav, S., Singhal, J., Zajac, E., Drake, K., Awasthi, Y.C., and Awasthi, S. (2005) Depletion of RLIP76 sensitizes lung cancer cells to doxorubicin. Biochem. Pharmacol. 70:481-488.

Awasthi, S., Singhal, S.S., Yadav, S., Singhal, J., Drake, K., Nadkar, A., Zajac, E., Wickramarachchi, D., Rowe, N., Yacoub, A., Boor, P., Dwivedi, S., Dent, P., Jarman, W., John, B. and Awasthi, Y.C. (2005) RALBP1 is a major determinant of radiation sensitivity. Cancer Res. 65:6022-6028.

Singhal, S.S., Yadav, S., Singhal, J., Drake, K., Awasthi, Y.C. and Awasthi, S. (2005) The Role of PKCα and RLIP76 in Transport-mediated Doxorubicin-resistance in Lung Cancer. FEBS Lett. 579:4635-4641.

Singhal, S.S., Awasthi, Y.C. and Awasthi, S. (2006) Regression of Melanoma in a Murine Model by RLIP76 Depletion. Cancer Res. 66:2354-2360.

Singhal, S.S., Wickramarachchi, D., Singhal, J., Yadav, S., Awasthi, Y. C. and Awasthi, S. (2006) Determinants of differential doxorubicin sensitivity between SCLC and NSCLC. FEBS Lett. 580:2258-2264.

Singhal, S.S., Yadav, S., Singhal, J., Awasthi, Y.C. and Awasthi, S. (2006) Mitogenic and drug-resistance mediating effects of PKCα require RLIP76. Biochem. Biophys. Res. Commun. 348:722-727.

Singhal, S.S., Singhal, J., Nair, M.P., Lacko, A.G., Awasthi, Y.C. and Awasthi, S. (2007) Doxorubicin transport by RALBP1 and ABCG2 in lung and breast cancer. Int. J. Oncol. 30:717-725.

Singhal, S.S., Singhal, J., Yadav, S., Dwivedi, S., Boor, P., Awasthi, Y.C. and Awasthi, S. (2007) Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (RALBP1). Cancer Res. 67: (in-press).

Department of Chemistry and Biochemistry
The University of Texas at Arlington
Arlington, Texas 76019-0065, USA

Phone:  (817) 272-3171

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