Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Satraplatin is an orally bioavailable platinum analog that has activity in prostate cancer. JM118 is the most abundant species found in the plasma following the oral ingestion of satraplatin and has anti-tumor activity in vitro against cell lines that are resistant to cisplatin (DDP). The goal of the current study was to determine whether the activity of JM118 in some DDP-resistant cells can be explained by differences in the cellular pharmacology of the two drugs. The effect of each of the Cu transporters CTR1, ATP7A and ATP7B on sensitivity to the growth inhibitory effect of JM118 and its cellular pharmacology was examined to identify the characteristics of JM118 that distinguish it from DDP. These studies were performed using wild type and CTR1-/- homozygous knockout mouse embryo cells, and human Me32a Menkes disease fibroblasts that do not express either ATP7A or ATP7B plus sublines molecularly engineered to express either ATP7A (MeMNK cells) or ATP7B (MeWND cells). Knockout of the Cu influx transporter CTR1 in murine embryo cells increased their resistance to DDP and reduced its cellular accumulation but had no effect on sensitivity to JM118 or its uptake. In the case of DDP, forced expression of either of the two Cu efflux transporters, ATP7A or ATP7B, in Me32a cells rendered them resistant to DDP, increased whole cell accumulation of Pt but reduced the amount of Pt in DNA. In the case of JM118, forced expression of either ATP7A or ATP7B rendered Me32a cells resistant, increased not only whole cell Pt accumulation but also increased rather than decreased the amount of Pt in DNA. These results demonstrate that both ATP7A and ATP7B mediate resistance to JM118 as well as DDP and suggest that they sequester both DDP and JM118 into vesicular compartments within the cell resulting in enhanced whole cell accumulation and reduced cytotoxicity. We conclude that there are two important differences between DDP and JM118 with respect to the effect of Cu transporters on their cellular pharmacology. First, whereas CTR1 is involved in DDP accumulation it does not play a role in the uptake of JM118. Second, ATP7A and ATP7B, while they both mediate resistance, have opposite effects on the accumulation of Pt in DNA following exposure to the two drugs. ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in DNA following exposure to JM118. These results suggest that JM118 will retain activity in cells in which DDP resistance is due to the loss of CTR1, but not in cells in which resistance is due to enhanced expression of ATP7A or ATP7B.
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PMID:Modulation of the cellular pharmacology of JM118, the major metabolite of satraplatin, by copper influx and efflux transporters. 1617 May 71

The final steps in the absorption and excretion of copper at the molecular level are accomplished by 2 closely related proteins that catalyze the ATP-dependent transport of copper across the plasma membrane. These proteins, ATP7A and ATP7B, are encoded by the genes affected in human genetic copper-transport disorders, namely, Menkes and Wilson diseases. We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. Our results indicate that ATP7A is retained in the trans-Golgi network under copper-limiting conditions, but relocalized to a vesicular compartment adjacent to the basolateral membrane in intestines perfused with copper. The findings support the hypothesis that the basolateral transport of copper from the enterocyte into the portal blood may involve ATP7A pumping copper into a vesicular compartment followed by exocytosis to release the copper, rather than direct pumping of copper across the basolateral membrane.
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PMID:Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice. 1631 17

The P-type ATPases affected in Menkes and Wilson diseases, ATP7A and ATP7B, respectively, are key copper transporters that regulate copper homeostasis. The N termini of these proteins are critical in regulating their function and activity, and contain six copper-binding motifs MxCxxC. In this study, we describe the identification of glutaredoxin (GRX1) as an interacting partner of both ATP7A and ATP7B, confirmed by yeast two-hybrid technology and by co-immunoprecipitation from mammalian cells. The interaction required the presence of copper and intact metal-binding motifs. In addition, the interaction was related to the number of metal-binding domains available. GRX1 catalyses the reduction of disulphide bridges and reverses the glutathionylation of proteins to regulate and/or protect protein activity. We propose that GRX1 is essential for ATPase function and catalyses either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport.
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PMID:Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases. 1688 90

Copper deficiency during pregnancy results in early embryonic death and foetal structural abnormalities including skeletal, pulmonary and cardiovascular defects. During pregnancy, copper is transported from the maternal circulation to the foetus by mechanisms which have not been clearly elucidated. Two copper-transporting ATPases, Menkes (ATP7A; MNK) and Wilson (ATP7B; WND), are expressed in the placenta and both are involved in placental copper transport, as copper accumulates in the placenta in both Menkes and Wilson disease. The regulatory mechanisms of MNK and WND and their exact role in the placenta are unknown. Using a differentiated polarized Jeg-3 cell culture model of placental trophoblasts, MNK and WND were shown to be expressed within these cells. Distinct roles for MNK and WND are suggested on the basis of their opposing responses to insulin. Insulin and oestrogen increased both MNK mRNA and protein levels, altered the localization of MNK towards the basolateral membrane in a copper-independent manner, and increased the transport of copper across this membrane. In contrast, levels of WND were decreased in response to insulin, and the protein was located in a tight perinuclear region, with a corresponding decrease in copper efflux across the apical membrane. These results are consistent with a model of copper transport in the placenta in which MNK delivers copper to the foetus and WND returns excess copper to the maternal circulation. Insulin and oestrogen stimulate copper transport to the foetus by increasing the expression of MNK and reducing the expression of WND. These data show for the first time that MNK and WND are differentially regulated by the hormones insulin and oestrogen in human placental cells.
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PMID:Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells. 1730 Feb 24

The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.
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PMID:Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. 1711 90

P(1B)-type ATPases transport heavy metals (Cu+, Cu2+, Zn2+, Co2+, Cd2+, Pb2+) across membranes. Present in most organisms, they are key elements for metal homeostasis. P(1B)-type ATPases contain 6-8 transmembrane fragments carrying signature sequences in segments flanking the large ATP binding cytoplasmic loop. These sequences made possible the differentiation of at least four P(1B)-ATPase subgroups with distinct metal selectivity: P(1B-1): Cu+, P(1B-2): Zn2+, P(1B-3): Cu2+, P(1B-4): Co2+. Mutagenesis of the invariant transmembrane Cys in H6, Asn and Tyr in H7 and Met and Ser in H8 of the Archaeoglobus fulgidus Cu+-ATPase has revealed that their side chains likely coordinate the metals during transport and constitute a central unique component of these enzymes. The structure of various cytoplasmic domains has been solved. The overall structure of those involved in enzyme phosphorylation (P-domain), nucleotide binding (N-domain) and energy transduction (A-domain), appears similar to those described for the SERCA Ca2+-ATPase. However, they show different features likely associated with singular functions of these proteins. Many P(1B)-type ATPases, but not all of them, also contain a diverse arrangement of cytoplasmic metal binding domains (MBDs). In spite of their structural differences, all N- and C-terminal MBDs appear to control the enzyme turnover rate without affecting metal binding to transmembrane transport sites. In addition, eukaryotic Cu+-ATPases have multiple N-MBD regions that participate in the metal dependent targeting and localization of these proteins. The current knowledge of structure-function relationships among the different P(1B)-ATPases allows for a description of selectivity, regulation and transport mechanisms. Moreover, it provides a framework to understand mutations in human Cu+-ATPases (ATP7A and ATP7B) that lead to Menkes and Wilson diseases.
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PMID:The structure and function of heavy metal transport P1B-ATPases. 1721 55

Copper (Cu) plays a critical role in the developing foetus, but virtually nothing is known concerning the regulation of its uptake and metabolism in the placenta. In this issue of the Biochemical Journal, Hardman and colleagues, using a model of placental trophoblasts in culture, identify differential hormonal regulation of two copper-transporting ATPases; namely, those responsible for Menkes disease (ATP7A; MNK) and Wilson disease (ATP7B; WND). Insulin and oestrogen, which are essential during gestation, up-regulate MNK and this leads to trafficking of the MNK protein from the Golgi to the basolateral membrane, resulting in increased Cu efflux. At the same time, insulin decreased WND levels, and this leads to intracellular sequestration of the protein to a perinuclear region that reduces apical Cu release. As such, this results in a concerted flux of Cu from the basolateral surface of the trophoblast that would potentially be used by the developing foetus. An integrated model of vectorized Cu transport is proposed, which involves co-ordinated expression of transporters, organelle interactions and probable protein-protein interactions. The findings have wider implications for considering general models of intracellular metal transport.
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PMID:Differential regulation of the Menkes and Wilson disease copper transporters by hormones: an integrated model of metal transport in the placenta. 1710 27

We and others have shown that the copper transporters ATP7A and ATP7B play a role in cellular resistance to cis-diaminedichloroplatinum (II) (CDDP). In this study, we found that ATP7A transfection of Chinese hamster ovary cells (CHO-K1) and fibroblasts isolated from Menkes disease patients enhanced resistance not only to CDDP but also to various anticancer drugs, such as vincristine, paclitaxel, 7-ethyl-10-hydroxy-camptothecin (SN-38), etoposide, doxorubicin, mitoxantron, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11). ATP7A preferentially localized doxorubicin fluorescence to the Golgi apparatus in contrast to the more intense nuclear staining of doxorubicin in the parental cells. Brefeldin A partially and monensin completely altered the distribution of doxorubicin to the nuclei in the ATP7A-expressing cells. ATP7A expression also enhanced the efflux rates of doxorubicin and SN-38 from cells and increased the uptake of SN-38 in membrane vesicles. These findings strongly suggested that ATP7A confers multidrug resistance to the cells by compartmentalizing drugs in the Golgi apparatus and by enhancing efflux of these drugs, and the trans-Golgi network has an important role of ATP7A-related drug resistance. ATP7A was expressed in 8 of 34 (23.5%) clinical colon cancer specimens but not in the adjacent normal epithelium. Using the histoculture drug response assay that is useful for the prediction of drug sensitivity of clinical cancers, ATP7A-expressing colon cancer cells were significantly more resistant to SN-38 than ATP7A-negative cells. Thus, ATP7A confers resistance to various anticancer agents on cancer cells and might be a good index of drug resistance in clinical colon cancers.
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PMID:Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer. 1751 Apr 16

Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.
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PMID:Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. 1753 Nov 89

Mutations in the copper-transporter ATP7A lead to severe neurodegeneration in the mottled brindled hemizygous male (MoBr/y) mouse and human patients with Menkes disease. Our earlier studies demonstrated cell-type- and -stage-specific changes in ATP7A protein expression during postnatal neurodevelopment. Here we examined copper and cuproenzyme levels in MoBr/y mice to search for compensatory responses. While all MoBr/y neocortical subcellular fractions had decreased copper levels, the greatest decrease (8-fold) was observed in cytosol. Immunostaining for ATP7A revealed decreased levels in MoBr/y hippocampal pyramidal and cerebellar Purkinje neurons. In contrast, an upregulation of ATP7A protein occurred in MoBr/y endothelial cells, perhaps to compensate for a lack of copper in the neuropil. MoBr/y astrocytes and microglia increased their physical association with the blood-brain barrier. No alterations in ATP7A levels were observed in ependymal cells, arguing for specificity in the alteration observed at the blood-brain barrier. The decreased expression of ATP7A protein in MoBr/y Purkinje cells was associated with impaired synaptogenesis and dramatic cytoskeletal dysfunction. Immunoblotting failed to reveal any compensatory increase in levels of ATP7B. While total levels of several cuproenzymes (peptide-amidating monooxygenase, SOD1, and SOD3) were unaltered in the MoBr/y brain, levels of amidated cholecystokinin (CCK8) and amidated pituitary adenylate cyclase-activating polypeptide (PACAP38) were reduced in a tissue-specific fashion. The compensatory changes observed in the neurovascular unit provide insight into the success of copper injections within a defined neurodevelopmental period.
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PMID:Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease. 1758 65


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