BIO: Education: BSc (Biochemistry); PhD (Pharmacology) Queen’s; Fogarty Postdoctoral Fellowship, Laboratory of Molecular Carcinogenesis, NIH, Bethesda, MD (USA). Current: Professor, Department of Pathology & Molecular Medicine; Professor (cross-appointed), Department of Biomedical & Molecular Sciences. Bracken Chair of Genetics & Molecular Medicine, Tier 1 Canada Research Chair in Cancer Biology. Elected Fellow of the Royal Society of Canada and the Canadian Academy of Health Sciences.
We are interested in membrane transport proteins and their roles in human health and disease. Most of our focus is on understanding the mechanisms of drug sensitivity and resistance, especially those mediated by members of the ATP-binding cassette (ABC) superfamily of transmembrane proteins.
Multidrug Resistance Protein (MRP1) [gene symbol ABCC1] is a 190 kDa plasma membrane protein that can confer multidrug resistance on previously sensitive tumour cells. It does this primarily by reducing the drug concentration in cells by actively pumping drugs out. Low levels of MRP1 are also found in normal cells where it influences how drugs used to treat cancer and other human diseases are distributed to various organs in the body. Thus MRP1 can protect normal tissues by acting as a barrier and impeding entry of foreign chemicals, including environmental toxins. Many organic anions (including glutathione (GSH) and glucuronide conjugated xenobiotics) are also transported by MRP1. And finally, MRP1 also mediates the cellular efflux of important physiological molecules such as the pro-inflammatory signalling molecule, cysteinyl leukotriene LTC4, and the ubiquitous antioxidant GSH.
Ongoing MRP1-related projects include: (i) investigations of how GSH affects the structure and activity of MRP1; (ii) mapping of the drug binding sites on MRP1; (iii) investigation of novel compounds and naturally occurring compounds that are substrates or modulators of MRP1 activity; (iv) identifying protein-protein interactions that affect the activity and/or cellular localization of MRP1; and (v) investigations of ABCC1/MRP1 polymorphisms that affect drug efficacy or toxicity.
We are also interested in the structural and functional differences between MRP1 and its homologs MRP2, MRP3 and MRP4. MRP4 is of particular interest because it effluxes antiviral drugs as well as the signalling molecules cAMP and prostaglandin E2. In epithelial and endothelial (ie polarized) cells, MRP4 has the unusual ability to localize to different membranes (apical versus basolateral) depending on the type of cell it is expressed.
Ongoing MRP4/ABCC4-related projects include: (i) investigation of protein-protein interactions that determine basolateral vs apical localization of MRP4 in polarized cells. (ii) identifying the structural determinants of MRP4 substrate specificity and membrane localization; and (iii) exploring the consequences of genetic variations of ABCC4.
The discoveries made by our group have been of both academic and commercial interest.
Representative Publications (mostly last 7 years) (selected from 228 total)
- S.P.C. Cole. Multidrug resistance protein 1 (MRP1, ABCC1): A “multitasking” ABC transporter. J. Biol. Chem. 289: 30880-30888 (2014). (invited review) (IF 4.60)
- S.P.C. Cole. Targeting the multidrug resistance protein (MRP1, ABCC1): past, present and future. Ann. Rev. Pharmacol. Toxicol. 54: 95-117 (2014). (invited review) (IF 21.6)
- A.J. Slot, S.V. Molinski and S.P.C. Cole. Multidrug resistance proteins. Essays Biochem. 50: 179-207 (2011).
- S.P.C. Cole and R.G. Deeley. Transport of glutathione and glutathione conjugates by MRP1. Trends Pharm. Sci. 27: 438-446 (2006).
- G. Conseil, R.G. Deeley and S.P.C. Cole. Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters. Pharmacogenet. Genomics 15: 523-533 (2005).
- J. Park, J-O. Kwak, B. Riederer, U. Seidler, S.P.C. Cole, H.J. Lee and M.G. Lee. Na+/H+ exchanger regulatory factor 3 is critical for multidrug resistance protein 4-mediated drug efflux in the kidney. J. Am. Soc. Nephrol. 25: 727-736 (2014). [Highlighted in Nat. Rev. Nephrol. 10: 183 (2014)].
- L. Cheung, C.L. Flemming, F. Watt, N. Masada, D.M. Yu, T. Huynh, G. Conseil, A. Tivnan, A. Polinsky, A.V. Gudkov, M.A. Munoz, A. Vishvanath, D.M. Cooper, M.J. Henderson, S.P.C. Cole, J.I. Fletcher, M. Haber and M.D. Norris. High-throughput screening identifies Ceefourin-1 and Ceefourin-2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Biochem. Pharmacol. 91: 97-108 (2014).
- D. Jin, T.T. Ni, J. Sun, H. Wan, J.D. Amack, G. Yu, J. Fleming, C. Chiang, W. Li, A. Papierniak, S. Cheepala, G. Conseil, S.P.C. Cole, B. Zhou, I.A. Drummond, J.D. Schuetz, J. Malicki and T.P. Zhong. Prostaglandin signaling regulates ciliogenesis by modulating intraflagellar transport. Nat. Cell. Biol. 16:841-851 (2014). [Highlighted in News & Views, P. Barbry, L.E. Zaragosi. An ABC of ciliogenesis. Nat. Cell Biol. 16: 826-827 (2014)].
- S.H. Iram and S.P.C. Cole. Differential functional rescue of Lys513 and Lys516 processing mutants of MRP1 (ABCC1) by chemical chaperones reveals different domain-domain interactions of the transporter. Biochim. Biophys. Acta 1838: 756-765 (2014).
- R.L. Myette, G. Conseil, S.P. Ebert, B. Wetzel, M.R. Detty and S.P.C. Cole. Chalcogenopyrylium dyes as differential modulators of organic anion transport by MRP1, MRP2 and MRP4. Drug Metab. Dispos. 41: 1231-1239 (2013).
- G. Conseil and S.P.C. Cole. Two polymorphic variants of ABCC1 selectively alter drug resistance and inhibitor sensitivity of the multidrug and organic anion transporter MRP1. Drug Metab. Dispos. 41:2187-2196 (2013).
- S.H. Iram and S.P.C. Cole. Expression and function of human MRP1 (ABCC1) is dependent on amino acids in cytoplasmic loop 5 and its interface with nucleotide binding domain 2. J. Biol. Chem. 286: 7202-7213 (2011).
- M. Pajic, J. Muray, G.M. Marshall, S.P.C. Cole, M.D. Norris and M. Haber. ABCC1/G2012T single nucleotide polymorphism is associated with patient outcome in primary neuroblastoma and altered stability of the ABCC1 gene transcript. Pharmacogenet. Genomics 21: 270-279 (2011).
- K. Maeno, A. Nakajima, G. Conseil, A. Rothnie, R.G. Deeley and S.P.C. Cole. Molecular basis for reduced estrone sulfate transport and altered modulator sensitivity of TM6 and TM17 mutants of MRP1 (ABCC1). Drug Metab. Dispos. 37: 1411-1420 (2009).
- Md. T. Hoque, G. Conseil and S.P.C. Cole. Involvement of NHERF1 in apical membrane localization of MRP4 in polarized kidney cells. Biochem. Biophys. Res. Commun. 379: 60-64 (2009).
- Md. T. Hoque and S.P.C. Cole. Downregulation of NHERF1 increases expression and function of multidrug resistance protein 4 (MRP4). Cancer Res. 68: 4802-4809 (2008).
- A. Rothnie, G. Conseil, A.Y.T. Lau, R.G. Deeley and S.P.C. Cole. Mechanistic differences between GSH transport by MRP1 (ABCC1) and GSH modulation of MRP1-mediated transport. Mol. Pharmacol. 74: 1630-1640 (2008).
- A. Rothnie, R. Callaghan, R.G. Deeley and S.P.C. Cole. Role of GSH in estrone sulfate binding and translocation by the multidrug resistance protein 1 (MRP1, ABCC1). J. Biol. Chem. 281: 13906-13914 (2006)
- I.J. Létourneau, R.G. Deeley and S.P.C. Cole. Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1). Pharmacogenet. Genomics 15: 647-657 (2005).
- P. Wu, C.J. Oleschuk, Q. Mao, B.O. Keller, R.G. Deeley and S.P.C. Cole. Analysis of human multidrug resistance protein 1 (ABCC1) by matrix-assisted laser desorption ionization/time of flight mass spectrometry: toward identification of leukotriene C4 binding sites. Mol. Pharmacol. 68: 1455-1465 (2005).
- K. Koike, G. Conseil, E.M. Leslie, R.G. Deeley and S.P.C. Cole. Identification of proline residues in the core cytoplasmic and transmembrane regions of multidrug resistance protein 1 (MRP1/ABCC1) important for transport function, substrate specificity, and nucleotide interactions. J. Biol. Chem. 279:12325-12336 (2004).
- E.M. Leslie, R.G. Deeley and S.P.C. Cole. Bioflavonoid stimulation of glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). Drug Metab. Dispos. 31: 11-15 (2003).
- A. Haimeur, R.G. Deeley and S.P.C. Cole. Charged amino acids in the sixth transmembrane helix of multidrug resistance protein 1 (MRP1) are critical determinants of transport activity. J. Biol. Chem. 277:41326-41333 (2002).
- E.M. Leslie, K. Ito, P. Upadhyaya, S.S. Hecht, R.G. Deeley and S.P.C. Cole. Transport of the ß-O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1/ABCC1): Requirement for glutathione or a non-sulfur-containing analog. J. Biol. Chem. 276: 27846-27854 (2001).
- S.P.C. Cole, G. Bhardwaj, J.H. Gerlach, J.E. Mackie, C.E. Grant, K.C. Almquist, A.J. Stewart, E.U. Kurz, A.M.V. Duncan, and R.G. Deeley. Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line. Science 258: 1650-1654 (1992). [2,476 citations-02/2014]