The ABC of ABCs: multidrug resistance and genetic diseases.

Abstract

ATP-binding cassette (ABC) proteins comprise one the largest protein families, because thousands of distinct genes are known to operate in all living cells and organisms from bacteria to man. Most ABC proteins act as transporters, required for a remarkable variety of membrane translocation processes through both efflux and uptake. ABC substrates include ions, heavy metals, carbohydrates, amino acids, oligopeptides, steroids, glucocorticoids, phospholipids, cholesterol, mycotoxins, antibiotics, drugs, pigments, peptide pheromones and even large proteins. Most strikingly, ABC proteins also function as receptors, ion channels, regulators of channels, nutrient sensors and even membrane-bound proteases. However, the mechanism(s) by which evolutionary and structurally conserved ABC proteins can fulfill such functional diversity remains an intriguing and as yet unsolved mystery. The P-glycoprotein (P-gp), multidrug resistancerelated protein (MRP) and breast cancer resistance protein (BCRP) subfamilies have been implicated in multidrug resistance (MDR) phenomena in cancer. Similarly, many orthologs in parasites, fungi and bacteria mediate anti-infective resistance. The clinical significance and contribution of P-gp to antitumor resistance, as well as approaches to overcome MDR in tumors by specific P-gp inhibitors, is more than ever a matter of intense dispute. What stands undisputed is that defective human ABC proteins cause important genetic disorders such as cystic fibrosis, macular dystrophy, hepatic cholestasis, the familial hyperinsulinemic hypoglycemia of infancy, lung dysfunction, connective tissue degeneration, atherosclerosis and even gout. This medical relevance of ABC proteins prompted the first FEBS Advanced Lecture Course in 1997 in Austria. Ever since, biennial FEBS courses, and then the first FEBS Special Meeting on ABC Proteins in 2006, have followed. ABC2010, organized by Kazumitsu Ueda, Susan PC Cole, Susan Michaelis and Karl Kuchler, was the latest in this successful series. In fact, the Austrian ABC meeting has become the most recognized gathering point for the ABC community, and many key collaborations in the field have originated in Innsbruck. Despite intense research efforts in basic and clinical research, as well as in drug discovery, a molecular understanding of the function mechanism of a single human ABC transporter appears elusive. The technical difficulties of studying intrinsic membrane proteins offer one explanation, the painfully slow process in getting high-resolution crystal structures is another. A few elegant, and in some instances debated, structures of ABC transporters have emerged, but the field needs many more (dynamic) structures to unravel common as well as ABC-protein-specific principles of function. FEBS and many other sponsors recognize the importance of the field and provided generous support for ABC2010; they will do so also for ABC2012, the next ABC meeting to take place in Innsbruck (http:// www.febs-abc2012.org). This minireview series, which is based on some exciting findings presented at ABC2010, discusses state-ofthe-art knowledge of hallmark members of the ABCA, ABCC and ABCG families. Two reviews address ABCA1, which connects lipoprotein metabolism with inborn errors of cholesterol transport, and ABCA4, which is tightly linked to hereditary vision loss owing to its role in membrane lipid homeostasis and retinal recycling. Like P-gp, certain ABCC and ABCG members share a remarkable functional dichotomy. On the one hand, they are potentially detrimental, because their ectopic or misregulated expression causes clinical MDR in many malignant tissues. On the other hand, they are essential for physiological drug detoxification processes, especially in the liver, kidney, placenta, across the blood–brain barrier or in the intestinal lumen. Thus, another minireview addresses the ABCG family, in which the physiological substrate for ABCG2, urate, has been recently identified, disclosing its essential role in gout. The fourth minireview discusses ABCC members like the MRP transporters, which are implicated in clinical drug resistance, as well as drug absorption, deposition and hepatic detoxification.