Fungal ABC proteins: pleiotropic drug resistance, stress response and cellular detoxification.
A number of prominent genetic diseases are caused by mutations in genes encoding ATP-binding cassette (ABC) proteins (Ambudkar, Gottesmann, 1998). Moreover, several mammalian ABC proteins such as P-glycoprotein (P-gp) (Gottesman et al., 1995) and multidrug-resistance-associated proteins (MRPs) (Cole, Deeley, 1998) have been implicated in multidrug resistance (MDR) phenotypes of tumor cells highly resistant to many different anticancer drugs. The characteristics of MDR phenomena include the initial resistance to a single anticancer drug, followed by the development of cross-resistance to many structurally and functionally unrelated drugs. Similar mechanisms of MDR exist in pathogenic fungi, including Candida and Aspergillus (Vanden Bossche et al., 1998), and also in parasites such as Plasmodium and Leishmania (Ambudkar, Gottesmann, 1998), as well as in many bacterial pathogens (Nikaido, 1998). To dissect the mechanisms of MDR development and to elucidate the physiological functions of ABC proteins, many efforts have been made during the past decade. Importantly, yeast orthologues of mammalian disease genes made this unicellular eukaryote an invaluable model system for studies on the molecular mechanisms of ABC proteins, in order to better understand and perhaps improve treatment of ABC gene-related disease. In this review, we provide an overview of ABC proteins and pleiotropic drug resistance in the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. Furthermore, we discuss the role of ABC proteins in clinical drug resistance development of certain fungal pathogens.
Wolfger H, Mamnun YM, Kuchler K