Christine A. HrycynaProfessor—Biochemistry
Office: BRWN 3130D
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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.
Schematic diagram showing a hypothetical model of the ABC transporter human Pglycoprotein with 12 transmembrane (TM) domains and two ATP sites. In this diagram, each circle represents an amino acid residue with the filled blue circles representing the positions of mutations that alter substrate specificity. The pink squiggly lines are glycosylation sites; the ATP sites are circled with the Walker A and B consensus motifs and "C-region" dodecapeptide indicated in purple. The known sites of phosphorylation are marked with a red encircled "P" and the sites that are photoaffinity labeled with drug analogs are indicated with green brackets. MXR1 differs from P-glycoprotein in that it contains six transmembrane domains and one ATP site per subunit with the ATP site encoded before the TMs. MXR1 may function as a dimer or oligomer.
(Adapted from Gottesman et al., Annu. Rev. Genet. 29:607, 1995)
EducationB.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.
- Outstanding Undergraduate Teaching Award in Memory of Charles B. Murphy, 2007
- Teaching for Tomorrow Award, 2006
- Research Fellow National Cancer Institute, National Institutes of Health, 1998-2000
- The Jane Coffin Childs Memorial Fund for Medical Research Postdoctoral Fellow, 1994-97
- Hahne, K.;Vervacke, J. S.;Shrestha, L.;Donelson, J. L.;Gibbs, R. A.;Distefano, M. D.;Hrycyna, C. A., Evaluation of substrate and inhibitor binding to yeast and human isoprenylcysteine carboxyl methyltransferases (Icmts) using biotinylated benzophenone-containing photoaffinity probes . Biochemical and Biophysical Research Com 2012 , 423 , 98-103.
- Kuriakose, J.;Hrycyna, C. A.;Chmielewski, J., Click chemistry-derived bivalent quinine inhibitors of P-glycoprotein-mediated cellular efflux . Bioorganic & Medicinal Chemistry Letters 2012 , 22 , 4410-4412.
- Namanja, H. A.;Emmert, D.;Davis, D. A.;Campos, C.;Miller, D. S.;Hrycyna, C. A.;Chmielewski, J., Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-Glycoprotein at the Blood-Brain Barrier with Prodrug Abacavir Dimers . Journal of the American Chemical Society 2012 , 134 , 2976-2980.