The ABC transporter Abcg2/Bcrp: Role in hypoxia mediated survival Partha Krishnamurthy & John D. Schuetz* Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 332 N. Lauderdale Ave., Memphis, 38105-2794, TN, USA; *Author for correspondence (Tel: 901-495-2174; Fax: 901-525-6869; E-mail: John.schuetz@stjude.org) Key words: ABC-transporter, BCRP, hypoxia, heme, porphyrins Abstract ABC (ATP-binding cassette) transporters have diverse roles in many cellular processes. These diverse roles require the presence of conserved membrane spanning domains and nucleotide binding domains. Bcrp (Abcg2) is a member of the ATP binding cassette family of plasma membrane transporters that was originally discovered for its ability to confer drug resistance in tumor cells. Subsequent studies showed Bcrp expression in normal tissues and high expression in primitive stem cells. Bcrp expression is induced under low oxygen conditions consistent with its high expression in tissues exposed to low oxygen environments. Moreover, Bcrp interacts with heme and other porphyrins. This finding and its regulation by hypoxia suggests it may play a role in protecting cells/tissue from protoporphyrin accumulation under hypoxia. These observations are strengthened by the fact that porphyrins accumulate in tissues of the Bcrp knockout mouse. It is possible that humans with loss of function Bcrp alleles may be more susceptible to porphyrin- induced phototoxicity. We propose that Bcrp plays a role in porphyrin homoeostasis and regulates survival under low oxygen conditions. Abbreviations: ABC – ATP binding cassette; BSEP – Bile salt export pump; Bcrp – Breast cancer resistance protein; CFTR – Cystic fibrosis transmembrane conductance regulator; DFO – Desferoxamine; HIF – Hypoxia inducible factor; NBD – Nucleotide-binding domain; PFIC – Progressive familial intrahepatic cholestasis; PPIX – Protoporphyrin IX; SNP – Single nucleotide polymorphism; TMD – Transmembrane domain. ABC transporters have conserved domains ABC (ATP-binding cassette) transporters are a family of proteins present in all known living species, with approximately 1100 different proteins described in the literature and public databases. ABC proteins contain two highly conserved domains as a combination of a con- served cytoplasmic ATP-binding (ABC) domain and divergent hydrophobic transmembrane domains (TMDs) . The ABC domain consists of three highly conserved sequence motifs, the Walker A and B motifs and the ABC signature, or the so called Walker C motif. The ABC signature motif is unique to ABC proteins and distinguishes them from other ATP-binding pro- teins. In mammals the functionally active ABC proteins consist of at least four such domains, two TMDs and two ABCs. These domains may be present within one polypeptide chain (‘full transporters’), or within two separate proteins (‘half transporters’). In this latter case functional ABC transporters need the dimerization of spe- cific half transporters. BioMetals (2005) 18:349–358 Ó Springer 2005 DOI 10.1007/s10534-005-3709-7