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Dr. Roger G. Deeley

Roger G. Deeley, Ph.D.

Email: deeleyr@queensu.ca
Office Phone:  613-533-6626
Lab:  613-533-2979
Fax:  613-533-6830


  • Professor of Pathology & Molecular Medicine, Oncology, and Biochemistry
  • Stauffer Research Professor of Basic Oncology
  • Director, Division of Cancer Biology & Genetics
  • Director, Cancer Research Institute
  • BSc, PhD, University of Sheffield

Dr. Deeley's Lab

Our research involves a comprehensive range of studies of the structure, mechanism of action, regulation of expression and subcellular trafficking of several members of the ATP Binding Cassette (ABC) superfamily of transmembrane transporters. We are particularly interested in the Multidrug Resistance Protein (MRP) subfamily of ABC transporters, specifically, ABCC/MRP1, 2 and 3, and another member of the superfamily, ABCA1.
The ABC transporters are a large and ancient superfamily of integral membrane proteins which characteristically span the membrane multiple times. Typically, they use the energy of ATP hydrolysis to actively transport substrates across various cell membranes. These substrates range in size and structure from ions and small molecule drugs to large polypeptides. Several members of the superfamily, including some MRPs, have been implicated in the clinical development of multidrug resistance, a major obstacle to successful systemic treatment of many solid and haematological tumors. In addition, mutations in a number of ABC proteins are responsible for inherited disorders, such as cystic fibrosis, congenital hyperinsulinemia of infancy, the connective tissue disease Pseudoxanthoma elasticum and macular degeneration (Stargardt's Disease), as well as certain types of hyperbilirubinemia and other disorders involving cholesterol disposition, such as Tangier disease, which is caused by defects in ABCA1.

Multidrug Resistance Proteins (MRPs)

The MRPs comprise one of the largest subfamilies of the ABC superfamily. We discovered the first of these proteins, human MRP1, in 1992 (see Cole et al,. Science (1992), below). Since then, the human MRP family has grown to include 12 additional members. MRP1 has been detected in many multidrug resistant cell lines and tissue samples from various types of cancer. The protein transports an exceptionally broad range of compounds. These include structurally diverse natural product drugs and toxins and their anionic conjugates, as well as many other anionic conjugates of physiological importance. One of the reasons that MRP1 can transport such a range of substrates is that in addition to ATP dependent direct transport of substrates, it is also capable of an ATP dependent co-transport mechanism involving reduced glutathione. As a consequence, high levels of MRP1 expression may have implications for the redox state of the cell. The two closest relatives of MRP1, MRP2 and MRP3, share some but not all of MRP1's transport characteristics. By making various hybrid and mutant MRPs, we have been able to gain considerable insight into the way in which the proteins recognize their substrates and to begin to understand how they couple the hydrolysis of ATP to the transport process. Some of the MRPs, including MRP1, 2 and 3, are unusual among ABC proteins in that they contain a third membrane spanning domain in addition to the two typically found in other members of the superfamily. We are pursuing a variety of approaches to better understand the higher order structure of the 17 transmembane helices in these three domains and to elucidate how they communicate with the protein's two cytosolic ATP binding domains. We are also using a number of molecular imaging techniques to identify regions of MRP1 that are important for targeting the protein to the basolateral regions of the plasma membrane and for controlling its recycling through various membrane compartments (see figure for confocal laser microscopic images of fluorescently tagged MRP1 localized with various subcellular markers). Finally, we have cloned the human, mouse and rat MRP1/mrp1 genes and are investigating mechanisms involved in their basal transcription, as well as how they may respond to oxidative and other forms of stress.

ABCA1

Mouse ABCA1 was identified in 1994 during a search for ABC transporters expressed in macrophages. Initial interest focussed on the possible role of the transporter in the macrophage mediated removal of remnants of cells undergoing programmed cell death, or apoptosis. Recognition of the physiological importance of the protein broadened significantly with the discovery in 1999 that defects in the ABCA1 gene were the underlying cause of Tangier disease, a rare inherited disorder that severely impairs the process by which cholesterol is transported from peripheral tissues back to the liver, so called reverse cholesterol transport. The role of ABCA1 in this process is believed to be to facilitate the efflux of free cholesterol to acceptor apolipoproteins such as ApoA1, which is the major protein component of high density lipoprotein. Precisely how ABCA1 stimulates the transfer of cholesterol to ApoA1 is not fully understood. Like the MRPs, ABCA1 has a number of unusual structural characteristics that distinguish it from most ABC transporters. We are now applying the techniques we have developed to study the MRPs to investigate the transport mechanism of ABCA1 and to determine the functional roles of some of its distinguishing structural features.


Selected Publications (2003-present)

(full list of publications shown in link at bottom of page)  

Nunoya, K., Grant, C., Zhang, D., Cole, S.P.C. and Deeley, R.G. Molecular cloning and pharmacological characterization of rat multidrug resistance protein 1 (rMRP1). Drug Metab. Dispos. 31: 1016-1026 (2003).

Zhang, D-W., Gu, H-M., Vasa, M., Muredda, M., Cole, S.P.C. and Deeley, R.G. Characterization of the role of polar amino residues within predicted transmembrane helix 17 in determining the substrate specificity of multidrug resistance protein 3 (ABCC3). Biochemistry 42: 9989-10000 (2003).

Payen, L., Gao, M., Westlake, C., Cole, S.P.C. and Deeley, R.G. Role of carboxylate residues adjacent to the conserved core Walker B motifs in the catalytic cycle of multidrug resistance protein 1 (ABCC1). J. Biol. Chem. 278: 38537-38547 (2003).

Muredda, M., Nunoya, K., Burtch-Wright, R.A., Kurz, E.U., Cole, S.P.C. and Deeley R.G. Cloning and characterization of the murine and rat mrp1 promoter regions. Mol. Pharmacol. 64: 1259-1269 (2003).

Zhang, D-W., Gu, H-M., Situ, D., Haimeur, A., Cole, S.P.C. and Deeley, R.G. Functional importance of polar and charged amino acid residues in transmembrane helix 14 of multidrug resistance protein 1 (MRP1/ABCC1): identification of an aspartate residue critical for conversion from a high to low affinity substrate binding site. J. Biol. Chem. 278: 46052-46063 (2003).

Westlake, C.J., Qian, Y-M., Gao, M., Vasa, M., Cole, S.P.C. and Deeley, R.G. Identification of the structural and functional boundaries of the multidrug resistance protein 1 cytoplasmic loop 3. Biochemistry 42: 14099-14113 (2003).

Zhang, D-W., Nunoya, K., Vasa, M., Gu, H-M., Theis, A., Cole, S.P.C. and Deeley, R.G. Transmembrane helix 11 of multidrug resistance protein 1 (MRP1/ABCC1): identification of polar amino acids important for substrate specificity and binding of ATP at nucleotide binding domain 1. Biochemistry 43: 9413-9425 (2004).

Westlake, C.J., Payen, L., Gao, M., Cole, S.P.C. and Deeley, R.G. Identification and characterization of functionally important elements in the multidrug resistance protein 1 COOH-terminal regions. J. Biol. Chem. 279: 53571-53583 (2004).

Westlake, C.J., Cole, S.P.C. and Deeley, R.G. Role of the NH2-terminal membrane spanning domain of MRP1/ABCC1 in protein processing and trafficking. Mol. Biol. Cell 16: 2483-2492 (2005).

Payen, L., Gao, M., Westlake, C., Theis, A., Cole, S.P.C. and Deeley, R.G. Functional interactions between nucleotide binding domains and LTC4 binding sites of multidrug resistance protein 1 (ABCC1). Mol. Pharmacol. 67: 1944-1953 (2005).

Deeley, R.G. and Cole, S.P.C. Substrate recognition and transport by multidrug resistance protein (MRP) 1 (ABCC1). FEBS Lett. 580: 1103-1111 (2006). (invited, peer-reviewed)

Zhang, D-W., Nunoya, K., Vasa, M., Gu, H-M., Cole, S.P.C. and Deeley, R.G.. Mutational analysis of polar amino acid residues within predicted transmembrane helices 10 and 16 of multidrug resistance protein 1 (ABCC1): effect on substrate specificity. Drug Metab. Disp. 34: 539-546 (2006). (ASPET James R. Gillette Drug Metabolism Best Paper of 2006).

Tam, S-P., Mok, L., Chimini, G., Vasa, M. and Deeley, R.G.. ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of the oxysterol by intact cells. Am. J. Physiol. Cell Physiol. 291: C490-502 (2006).

Cole, S.P.C. and Deeley, R.G. Transport of glutathione and glutathione conjugates by MRP1. Trends Pharm. Sci. 27: 438-446 (2006) (invited, peer- reviewed).

Deeley, R.G., Westlake, C. and Cole, S.P.C. Transmembrane transport of endo- and xenobiotics by the ATP-binding cassette multidrug resistance proteins (MRPs). Physiol. Rev. 86: 849-899 (2006) (invited, peer-reviewed).

 Bandler, P.E., Westlake, C.J., Grant, C.E., Cole, S.P.C. and Deeley, R.G.  Identification of regions in human multidrug resistance protein (MRP) 2 required for apical membrane localization. Mol. Pharmacol. 74: 9-19 (2008).

Grant, C.E.,  Gao, M., M.K. DeGorter, M.K., Cole, S.P.C. and Deeley, R.G.  Structural determinants of substrate specificity differences between human multidrug resistance protein (MRP) 1 (ABCC1) and MRP3 (ABCC3). Drug Metab. Dispos. 36: 2571-2581 (2008).

Qin, L., Zheng, J. Grant, C.E., Jia, Z., Cole, S.P.C. and Deeley, R.G.. Residues responsible for the asymmetric function of the nucleotide binding domains of multidrug resistance protein (MRP) 1. Biochemistry 47: 13952-13965 (2008).

1.          Rosenberg, M.F., Oleschuk, C.J., Wu, P. Mao, Q. Deeley, R.G. Cole, S.P.C. and R.C. Ford. Structure of a human multidrug transporter in an inward-facing conformation. J. Struct. Biol. 170: 540-547 (2010).

Qin, L., Tam, S-P. and Deeley, R.G. Effect of multiple cysteine substitutions on the functionality of human multidrug resistance protein 1 expressed in human embryonic kidney 293 cells: identification of residues essential for function. Drug Metab. Dispos. 40: 1403-1413 (2012).

Complete list of Dr. Deeley's Publications

Last updated: 26 Feb. 2013

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