Identification and Functional Expression of HAH1, a Novel Human Gene Involved in Copper Homeostasis

Abstract

To search for a mammalian homologue of ATX1, a human liver cDNA library was screened and a cDNA clone was isolated, which encodes a protein with 47% amino acid identity to Atx1p including conservation of the MTCXGC copper-binding domain. RNA blot analysis using this cDNA identified an abundant 0.5-kilobase mRNA in all human tissues and cell lines examined. Southern blot analysis using this same clone indicated that the corresponding gene exists as a single copy in the haploid genome, and chromosomal localization by fluorescence in situ hybridization detected this locus at the interface between bands 5q32 and 5q33. Yeast strains lacking copper/zinc superoxide dismutase (SOD1) are sensitive to redox cycling agents and dioxygen and are auxotrophic for lysine when grown in air, and expression of this human ATX1 homologue (HAH1) in these strains restored growth on lysine-deficient media. Yeast strains lacking ATX1 are deficient in high affinity iron uptake and expression of HAH1 in these strains permits growth on iron-depleted media and results in restoration of copper incorporation into newly synthesized Fet3p. These results identify HAH1 as a novel ubiquitously expressed protein, which may play an essential role in antioxidant defense and copper homeostasis in humans.

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

“…It has been documented that ATP7A and ATP7B sequestered platinum drugs from the cytoplasm into subcellular compartments, mainly vesicles localized to the trans-Golgi network (TGN) for subsequent efflux in a manner similar to their effects on copper (Klomp et al, 1997). This action led to reduced platinum cytotoxicity .…”

Delivering copper within plant cells

“…Once inside the post-Golgi vesicle, the copper can be insert ed into copper-requiring proteins as they make their way to the plasma membrane, the endomembrane system or to be secreted. A human homolog of ATXI, HUMAN ATX HOMOLOG (HAHI) (Figure Ib), has been found, indicating that this pathway is conserved in eukaryotes [14]. In d1is review we describe recent advances in the study of an intra cellular copper trafficking pathway in plants.…”

Binding of Copper(I) by the Wilson Disease Protein and Its Copper Chaperone

“…This process is dependent on interaction with Atox1, a copper chaperone that delivers Cu(I) ions to WND (6,7). At elevated copper concentrations, WND redistributes to cytoplasmic vesicles and mediates copper efflux from the cell (4,8).…”