Disease relevance of SLC31A1

• In contrast with the copper export P-type ATPases mutated in Wilson disease and Menkes disease, the localization of hCTR1 was not influenced by copper concentrations [1].
• Overexpression of hCTR1 in wild-type yeast leads to increased sensitivity to copper toxicity, and mice with a homozygous disruption at the Ctr1 locus die early during embryogenesis [1].
• Mammary gland Cu transport was highest during early lactation and was stimulated by suckling and hyperprolactinemia, which was associated with Ctr1 and Atp7A localization at the plasma membrane [2].
• This study confirms that DDP triggers the rapid loss of hCTR1 from ovarian carcinoma cells at clinically relevant concentrations [3].
• Expression, localisation and hormone regulation of the human copper transporter hCTR1 in placenta and choriocarcinoma Jeg-3 cells [4].

High impact information on SLC31A1

• A central player in copper homeostasis is the high-affinity integral plasma membrane copper transporter Ctr1 [5].
• Here, we highlight an important breakthrough in our understanding of how Ctr1 facilitates Cu(I) movement across membranes: the publication of structural details for human Ctr1 obtained from 2D crystallography and electron microscopy [5].
• Specifically, we demonstrate that EIN5 is a component of the ethylene signal transduction cascade acting downstream of CTR1 that is required for ethylene-mediated gene expression changes [6].
• Cisplatin also causes degradation and delocalization of Ctr1p and interferes with copper uptake in wild-type yeast cells [7].
• The link between Ctr1p and cisplatin transport may explain some cases of cisplatin resistance in humans and suggests ways of modulating sensitivity and toxicity to this important anticancer drug [7].

Biological context of SLC31A1

• Characterization of the hCTR1 gene: genomic organization, functional expression, and identification of a highly homologous processed gene [8].
• Here, we have determined the DNA sequence of the exon-intron borders of the hCTR1 structural gene and report that the coding sequence is disrupted by three introns, all of which comply with the GT/AG rule [8].
• Identification of methionine-rich clusters that regulate copper-stimulated endocytosis of the human Ctr1 copper transporter [9].
• The (SSC) SLC31A1 gene is organized in four exons and spans an approximately 2.3 kb genomic region [10].
• This region shows conservation of synteny with human chromosome 9, where the human SLC31A1 (CTR1) gene has been localized [10].

Anatomical context of SLC31A1

• Both approaches indicated that hCTR1 contains three transmembrane domains and that the N-terminus of hCTR1, which contains several putative copper-binding sites, is localized extracellularly, whereas the C-terminus is exposed to the cytosol [11].
• Furthermore, human fibroblasts, transfected with hCTR1 cDNA, were shown to have a dramatically increased capacity for (64)Cu uptake, indicating that the hCtr1 protein is functional in copper uptake in human cells [8].
• Stable plasma membrane levels of hCTR1 mediate cellular copper uptake [12].
• In some cell lines, hCTR1 was located predominantly in an intracellular vesicular perinuclear compartment, and in others hCTR1 was located predominantly at the plasma membrane [1].
• Inhibition of endocytosis by methyl-beta-cyclodextrin caused a partial redistribution of hCTR1 to the cell surface of HeLa cells [1].

Associations of SLC31A1 with chemical compounds

• We have used indirect immunofluorescense studies and glycosylation-site insertion and deletion mapping to characterize the topology of human copper transporter 1 (hCTR1), the putative human high-affinity copper-import protein [11].
• Cisplatin stabilizes a multimeric complex of the human Ctr1 copper transporter: requirement for the extracellular methionine-rich clusters [13].
• The results highlight the relevance of CTR1 for cisplatin sensitivity as there is a clear relationship between lower CTR1 expression, intracellular concentration, DNA platination and cytotoxicity of cisplatin in both resistant cell lines [14].
• Ctr1, the major copper influx transporter, has been convincingly demonstrated to transport cisplatin and its analogues, carboplatin, and oxaliplatin [15].
• DDP-induced loss of hCTR1 was blocked by the proteasome inhibitors lactacystin, proteasome inhibitor 1, and MG132 [3].
• Expression of amino-terminal truncations and alanine substitution mutants of hCTR1 in HEK293 and MDCK cells localized the site of O-linked glycosylation to Thr-27 [16].

Other interactions of SLC31A1

• An additional human gene similar to hCTR1, here named hCTR2, was identified in a database search [17].
• Biosynthetic studies using this antiserum revealed that hCTR1 was synthesized as a precursor protein of 28 kDa containing N-linked oligosaccharides, and is then converted to a mature protein of approx. 35 kDa, which is ubiquitously expressed [1].
• Gene expression of importer CTR1, and ATP7A and ATP7B efflux transporters (with and without cisplatin treatment) was investigated using quantitative real-time PCR and platinum concentrations were determined by flameless atomic absorption spectrometry [14].
• Using transfected cell lines, we show that both c-DDP and BBR3464 use the copper transporter hCTR1 to enter cells and to a lesser extent, the ATP7B transporter to exit cells [18].
• The major copper influx transporter, copper transporter 1 (hCTR1), controls the cellular accumulation of cisplatin in mammalian cells [19].

Analytical, diagnostic and therapeutic context of SLC31A1

• Western blots of hCTR1 in Sf9 cells showed expression levels 100-fold higher than in mammalian (HepG2) cells [20].
• Immunofluorescence studies showed that subcellular hCTR1 localization differed markedly between cell types [1].
• Among the 38 cases, 24 were diagnosed as schistosomiasis by the finding of eggs in feces, 13 were diagnosed by positive serological test with IHA or COPT, and only in one case, the diagnosis of schistosomiasis was doubtful before operation [21].
• The serological prevalence rate among Negrito Orang Asli in that study area was 9% for ELISA and 4% for COPT [22].

References