Hrycyna, Christine A. - Purdue University

个人简介

B.A., 1988, Middlebury College; Ph.D., 1993, University of California, Los Angeles; Postdoctoral Fellow, 1993-1998, National Cancer Institute, National Institutes of Health; The Jane Coffin Childs Memorial Fund for Medical Research Postdoctoral Fellow, 1994-1997.

研究领域

Our main research interests are in the field of multidrug resistance in human cancer. Although numerous cancers can be successfully treated with ablative surgery, radiotherapy or chemotherapy, many cancers are intrinsically resistant to anti-cancer drugs or become resistant through the course of treatment. This broad-based cellular resistance to anti-cancer drugs results, in large part, from expression of a 170 kDa multidrug transporter or P-glycoprotein, encoded by the multidrug resistance MDR1 gene in humans. Many different human cancers express the MDR1 gene at levels sufficient to confer multidrug resistance and it can be estimated that approximately 50% of human cancers will express the gene at some time during therapy. Therefore, it has become apparent that multidrug resistance in a clinical setting is an obstacle that must be overcome to treat cancers effectively. It is of obvious importance to fully understand how the transporter functions in order to combat this phenomenon clinically. Taking biochemical, molecular genetic, and cell biological approaches using both mammalian and microbial cell systems, the majority of our efforts focus on the elucidation of the mechanism of action of human P-glycoprotein and a related drug transporter MXR1 that is involved in mitoxantrone resistance. Ultimately, a complete understanding of these proteins could lead to the development of new inhibitory agents that could greatly facilitate the treatment of a large number of human cancers. These drug transporters are members of a large superfamily of membrane transporters called the ATP-Binding Cassette (ABC) family. Through work with Pglycoprotein and MXR1, our interest in the field of transporters and their relation to cellular function and human disease has developed. In the future, we are also interested in identifying and studying other ABC transporters possibly linked to human diseases. We hope to gain further understanding of the basic mechanism of action of ABC transporters to elucidate their cellular functions both normally and in potential disease states.

近期论文

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Hodges, H. B., Zhou, M., Anderson, J. L., Thompson, D. T. and Hrycyna, C.A.*: Inhibition of Membrane-Spanning Metalloproteins by Hydrophobic Metal Chelators, Bioconjugate Chemistry, 16: 490 - 493, 2005. Tarasova, N. I., Rishi S., Tarasov, S. G., Kosakowska-Cholody, T., Hrycyna, C.A.*, Gottesman, M. M. and Michejda, C. J.: Transmembrane inhibitors of P-glycoprotein, an ABC transporter, J. Med. Chem., 48: 3768 - 3775, 2005. Anderson, J. A., Henriksen, B., Gibbs, R. and Hrycyna, C.A.*: The Isoprenoid Substrate Specificity of Isoprenylcysteine Carboxylmethyltransferase: Development of Novel Inhibitors, J. Biol. Chem., 280: 29454 - 29461, 2005. Bhatia, A., Sch?efer, H. J., and Hrycyna, C.A.*: Oligomerization of the Human ABC Transporter, ABCG2: Evaluation of the Native Protein and Chimeric Dimers, Biochemistry, 44: 10893 - 10904, 2005. Geisler, M. , Blakeslee, J. J. , Bouchard, R. , Lee, O.R. , Vincenzetti, V. , Bandyopadhyay, A., Peer, W.A. , Bailly, A. , Richards, E. L. , Ejendal, K. F. K. , Smith, A. P., Baroux, C. , Grossniklaus, U. , M??ller, A. , Hrycyna, C. A, R. Dudler, Murphy, A. S. and Martinoia, E.: Active export of auxin by MDR-type ATP-binding cassette transporters of Arabidopsis thaliana, The Plant Journal, 44:179-194, 2005. Henriksen, B., Anderson, J. L., Hrycyna, C.A.*, and Gibbs, R. A.: Synthesis of Desthio Prenylcysteine Analogs: Sulfur is Important for Biological Activity, Bioorganic & Medicinal Chemistry Letters, 15:5080 a€“ 5083, 2005. Anderson, J. A. and Hrycyna, C.A.*: Structure and Biological role of the Isoprenylcysteine Protein Carboxyl Methyltransferase, The Enzymes, Vol. 24, Protein methyltransferases. Steven G. Clarke and Fuyuhiko Tamanoi, eds., Chapter 9: 245 - 272, 2006.42. Ejendal, F. K., Diop, N. K., Schweiger, L. C., and Hrycyna, C.A.*: The Nature of Amino Acid 482 of Human ABCG2 is Important for Substrate Transport and ATPase Activity but not for Substrate Binding, Protein Science, 15:1597 - 1607, 2006. Donelson, J. L., Hodges, H. B., MacDougall, D. D., Hrycyna, C.A.*, and Gibbs, R. A.*: Synthesis and Biological Evaluation of Amine-Modified Farnesyl Cysteine Analogs as Isoprenylcysteine Methyltransferase Inhibitors, Bioorganic and Medicinal Chemistry Letters, 2006. Pires, M., Hrycyna, C.A.*, and Chmielewski, J. A.*: Bivalent Inhibitors of the Human Multidrug Transporter P-glycoprotein, Biochemistry, 45:11695-11702, 2006. Gelb, M. H.*, S. Michaelis, Hrycyna, C.A., Waldman, H. Brunsveld, L., Tamanoi, F. and Van Voorhis, W.: Therapeutic intervention based on protein prenylation and associated modifications, Nature Chemical Biology, 2:518 - 528, 2006. Febo-Ayala, W., Morera-Felix, Hrycyna, C.A.*, and Thompson, D. T.*: Functional Reconstitution of the Integral Membrane Enzyme, Isoprenylcysteine Carboxyl Methyltransferase, in Synthetic Bolalipid Vesicles, Biochemistry, 45:14683 - 14694, 2006. Takenaka, K., Morgan, J. A., Krishnamurthy, P., Lan, L., Adachi, M., Stewart, C. F., Sun, D., Leggas, M., Ejendal, K. F. K., Hrycyna, C.A., and Schuetz, J. D.*: Substrate Overlap between Mrp4 and Abcg2/Bcrp Affects Purine Analog Drug Cytotoxicity and Tissue Distribution, Cancer Research, 67:6965-6972, 2007. Coffinier, C.*, Hudon, S., Farber, E., Chang, S. Y., Hrycyna, C.A.*, Young, S. G.*, and Fong, L. G.*: From the Cover: HIV Protease Inhibitors Block the Zinc Metalloproteinase ZMPSTE24 and Lead to an Accumulation of Prelamin A in Cells, Proc. Natl. Acad. Sci., 33: 13432-13437, 2007. Coffinier, C., Hudon, S.E., Lee, R., Farber, E.A., Nobumori, C., Miner, J.H., Andres, D.A., Spielmann, H.P., Hrycyna, C.A., Fong, L.G., and Young, S.G.*: A Potent HIV Protease Inhibitor, Darunavir, Does not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-Prelamin A in Cells, J. Biol. Chem., 15: 9797-804, 2008. Hudon, S.E., Coffinier, C., Michaelis, S., Fong, L.G., Young, S.G., and Hrycyna, C.A.*: HIV Protease Inhibitors Block the Enzymatic Activity of Purified Ste24p, Biochem. Biophys. Res. Comm. 374: 365-368, 2008. Pires, M.M., Emmert, D., Hrycyna, C.A.*, and Chmielewski, J.*: Inhibition of P-glycoprotein-Mediated Taxol Resistance by Reversibly-Linked Quinine Homodimers, Molecular Pharmacology, 75: 92 - 100, 2009. Donelson, J.L., Hodges-Loaiza, H.B., Henriksen, B.S., Hrycyna, C.A., and Gibbs, R.A.: Solid Phase Synthesis of Prenylcysteine Analogs, J. Org. Chem., 74: 2975 - 2981, 2009. Namanja, H.A., Emmert, D., Pires, M.M., Hrycyna, C.A.*, and Chmielewski, J.*: Inhibition of Human P-glycoprotein Transport and Substrate Binding Using a Galantamine Dimer, Biochem. Biophys. Res. Comm., 388: 672 - 676, 2009. Griggs, A.M., Hahne, K., and Hrycyna, C.A.*: Functional Oligomerization of the Saccharomyces cerevisiae Isoprenylcysteine Carboxyl Methyltransferase, Ste14p, J. Biol. Chem., in press, 2010.