Gene amplification of the Menkes (MNK; ATP7A) P-type ATPase gene of CHO cells is associated with copper resistance and enhanced copper efflux

Camakaris, James; Petris, Michael J.; Bailey, Leanne; Shen, Peiyan; Lockhart, Paul J.; Glover, Thomas W.; Barcroft, Christine L.; Patton, J. S.; Mercer, Julian F. B.

doi:10.1093/hmg/4.11.2117

Cited by 168 publications

(152 citation statements)

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“…3B). These data are consistent with a report showing that the overexpression of MNK permit Chinese hamster ovary cells to tolerate highly toxic amounts of copper in their immediate environment (29) and also suggest that FKBP52 is functionally as well as biochemically linked to the Atox1/MNK (or WD) pathway. 100 nM FK506 pretreatment reproducibly blocked the early phase copper efflux in FKBP52 expressed cells (Fig.…”

Section: Fkbp52 and Copper Metabolism 27847supporting

confidence: 92%

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Sanokawa-Akakura

Dai

Akakura

et al. 2004

Journal of Biological Chemistry

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FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans-isomerase(PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library. We identified an interaction between FKBP52 domain I and Atox1, a copper-binding metallochaperone. Atox1 interacts with Menkes disease protein and Wilson disease protein (WD) and functions in copper efflux. The interaction between FKBP52 and Atox1 was observed in both glutathione S-transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506. Interestingly, the FKBP52/Atox1 interaction was enhanced when HEK 293T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, bathocuproine disulfate, suggesting that the interaction is regulated in part by intracellular copper. Overexpression of FKBP52 increased rapid copper efflux in 64 Cu-loaded cells, as did the overexpression of WD transporter. Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity. FKBP521 is a high molecular weight FK506-binding immunophilin first identified as a component of steroid hormone receptor heterocomplexes (1). Analysis of mRNA and protein levels has demonstrated that FKBP52 is widely expressed in mammalian tissues but particularly abundant in the nervous system (2, 3). Structurally, FKBP52 contains an N-terminal peptidylprolyl cis-trans-isomerase (PPIase) domain (domain I), a FKBP-like pseudo domain (domain II), three tetratricopeptide repeat (TPR) domains (domain III) that mediate proteinprotein interactions with HSP90, and a C-terminal domain calmodulin-binding site (domain IV) (4, 5).FKBP52 has been shown to play important roles in a diverse number of intracellular processes, but much research has focused on its involvement in steroid hormone regulation. FKBP52 regulates the maturation of steroid hormone receptor complexes through interactions between its TPR domain and HSP90 chaperones, which act as scaffolds for receptor assembly and are thought to enhance the affinity of estrogen receptor and the glucocorticoid receptor toward their ligands (1, 6). The PPIase domain of FKBP52 facilitates translocation of the activated steroid receptors to the nucleus by binding to cytoplasmic dynein (7). FKBP52 serves as a transcriptional regulator by repressing the activity of interferon regulatory factor-4 in immune cells (8) and heat-shock factor-1 in HeLa cells (9). FKBP52 has been implicated in the cardiotrophic effect of cardiotrophin-1 (10...

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Section: Fkbp52 and Copper Metabolism 27847supporting

confidence: 92%

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Sanokawa-Akakura

Dai

Akakura

et al. 2004

Journal of Biological Chemistry

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“…ATP7A (and ATP7B) has a dual role in the cell: apart from copperloading of enzymes in the secretory pathway, it is responsible for ATPdriven efflux of copper from the cells. 9 Under normal physiological copper concentrations ATP7A is localized to TGN, transporting copper into the lumen to the copper-dependent enzymes. Under increased copper concentrations ATP7A is translocated to the vesicles 10 or to the plasma membrane.…”

Section: Cellular Copper Metabolismmentioning

confidence: 99%

Menkes disease

Tümer

Møller²

2009

Eur J Hum Genet

314

276

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“…Copper-resistant rodent cell lines have been shown to overexpress the Menkes protein, supporting the concept that this protein functions to maintain cellular copper homeostasis (13). Saccharomyces cerevisiae deficient in CCC2, the yeast Menkes/Wilson disease gene homologue (14), are defective in high affinity iron transport due to the lack of copper incorporation into Fet3p, a multicopper oxidase homologous to human ceruloplasmin (15,16).…”

mentioning

confidence: 92%

Functional Expression of the Menkes Disease Protein Reveals Common Biochemical Mechanisms Among the Copper-transporting P-type ATPases

Payne

Gitlin

1998

Journal of Biological Chemistry

149

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Menkes disease is a fatal neurodegenerative disorder of childhood caused by the absence or dysfunction of a putative P-type ATPase encoded on the X chromosome. To elucidate the function of the Menkes disease protein, a plasmid containing the open reading frame of the human Menkes disease gene was constructed and used to transform a strain of Saccharomyces cerevisiae deficient in CCC2, the yeast Menkes/Wilson disease gene homologue. ccc2⌬ yeast are deficient in copper transport into the secretory pathway, and expression of a wild type human Menkes cDNA complemented this defect, as evidenced by the restoration of copper incorporation into the multicopper oxidase Fet3p. Site-directed mutagenesis demonstrated the essential role of four specific amino acids in this process, including a conserved histidine, which is the site of the most common disease mutation in the homologous Wilson disease protein. The expression of Menkes cDNAs with successive mutations of the conserved cysteine residues in the six aminoterminal MXCXXC metal binding domains confirmed the essential role of these cysteine residues in copper transport but revealed that each of these domains is not functionally equivalent. These data demonstrate that the Menkes disease protein functions to deliver copper into the secretory pathway of the cell and that this process involves biochemical mechanisms common to previously characterized members of this P-type ATPase family.

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Gene amplification of the Menkes (MNK; ATP7A) P-type ATPase gene of CHO cells is associated with copper resistance and enhanced copper efflux

Cited by 168 publications

References 0 publications

A Novel Role for the Immunophilin FKBP52 in Copper Transport

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Menkes disease

Functional Expression of the Menkes Disease Protein Reveals Common Biochemical Mechanisms Among the Copper-transporting P-type ATPases

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