Christine A. Hrycyna

Active Mentor - currently hosting PULSe students for laboratory rotations and recruiting PULSe students into the laboratory; serves on preliminary exam committees

Current Research Interests:

Our main research interests are in the field of multidrug resistance in human cancer. Although numerous cancers can be treated successfully with 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 multidrug transporters. Many of these transporters are members of the ATP-binding cassette (ABC) superfamily and require ATP hydrolysis for function. We study two of these pumps, the newly discovered protein, MXR1 as well as P-glycoprotein. Since a variety of different human cancers express these proteins at levels sufficient to confer multidrug resistance during therapy, it is important to understand how these transporters function in order to combat this phenomenon clinically. Taking biochemical, molecular genetic, biophysical and cell biological approaches, we focus on elucidating the molecular mechanisms of substrate recognition and how the energy of ATP hydrolysis is transduced into drug transport. A complete understanding of these proteins could lead to the development of new therapeutic agents that could greatly facilitate the treatment of a large number of human cancers.

We are also interested in the post-translational processing of eukaryotic proteins. Many proteins involved in signal transuction, such as the ras proteins, are modified at their C-termini, targeting them to the appropriate intracellular location where they function. These proteins are initially synthesized with a C-terminal -CaaX sequence (where C is cysteine, "a" is an aliphatic residue and "X" can be any number of amino acids) and undergo three serial reactions including isoprenylation of the cysteine, proteolysis of the three terminal amino acids (-aaX) and a-carboxyl methyl-esterification of the cysteine. Our lab is investigating the methyltransferase responsible for the final modification and the possible role reversible methylation plays in cellular trafficking and localization of -CaaX containing proteins. Interestingly, when oncogenic ras is not methylated, it is not properly localized and is no longer able to transform cells. Therefore, novel inhibitors of C-terminal isoprenylcysteine methylation may prove to be useful clinical anti-cancer agents.

Selected Publications:

Ejendal, K. F. and Hrycyna, C. A.: Multidrug Resistance and Cancer: The Role of the Human ABC Transporter ABCG2, Current Protein and Peptide Science, 3: 503 - 511, 2002.

Ejendal, F. K. and Hrycyna, C. A.: Differential Sensitivities of the Human ABC Transporters ABCG2 and P-glycoprotein to Cyclosporin A. Molecular Pharmacology, 67: 902 - 911, 2005.

Anderson, J. A., Frase, H., Michaelis, S., and Hrycyna, C. A.: Purification and Functional Reconstitution and Characterization of the Ste14p Isoprenylcysteine Methyltransferase. J. Biol. Chem 280: 7336 - 7345, 2005. Paper of the Week

Diop, N. K. and Hrycyna, C. A: N-linked Glycosylation of the Human ABC Transporter ABCG2 on Asparagine 596 is Not Essential for Expression, Transport Activity or Trafficking to the Plasma Membrane, Biochemistry, 44:5420 - 5429, 2005.

Wang, C., Leffler, L., Thompson, D. T. and Hrycyna, C. A.: A General Fluorescence-based Coupled Assay for S-Adenosylmethionine-dependent Methyltransferases, Biochem. Biophys. Res. Comm., 331: 351 - 356, 2005.

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.

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., Schäfer, 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.

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 - 5083, 2005.