Fungal ABC proteins: pleiotropic drug resistance, stress response and cellular detoxification

A number of prominent genetic diseases are caused by mutations in genes enc oding ATP-binding cassette (ABC) proteins (Ambudkar, Gottesmann, 1998). Mor eover, several mammalian ABC proteins such as P-glycoprotein (P-gp) (Gottes man et al., 1995) and multidrug-resistance-associated proteins (MRPs) (Cole , Deeley, 1998) have been implicated in multidrug resistance (MDR) phenotyp es 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 s tructurally and functionally unrelated drugs. Similar mechanisms of MDR exi st in pathogenic fungi, including Candida and Aspergillus (Vanden Bossche e t al., 1998), and also in parasites such as Plasmodium and Leishmania (Ambu dkar, Gottesmann, 1998), as well as in many bacterial pathogens (Nikaido, 1 998). To dissect the mechanisms of MDR development and to elucidate the phy siological functions of ABC proteins, many efforts have been made during th e past decade. Importantly, yeast orthologues of mammalian disease genes ma de this unicellular eukaryote an invaluable model system for studies on the molecular mechanisms of ABC proteins, in order to better understand and pe rhaps improve treatment of ABC gene-related disease. In this review, we pro vide an overview of ABC proteins and pleiotropic drug resistance in the bud ding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyc es pombe. Furthermore, we discuss the role of ABC proteins in clinical drug resistance development of certain fungal pathogens. (C) 2001 Editions scie ntifiques et medicales Elsevier SAS.