Sequence, mapping and disruption of CCC2, a gene that cross‐complements the Ca2+‐sensitive phenotype of csg1 mutants and encodes a P‐type ATPase belonging to the Cu2+‐ATPase subfamily

Fu, Daotian; Beeler, Troy; Dunn, Teresa M.

doi:10.1002/yea.320110310

Cited by 163 publications

(110 citation statements)

References 24 publications

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“…CadA and ZntA are members of the superfamily of P-type cation-translocating ATPases, but belong to a group of soft metal transporters that includes bacterial enzymes such as the CopA Cu(I) pump (23), the yeast CCC2 Cu(I) pump (24), and the human Cu(I)-transporting ATPases such as MNK (25) and WND (26). The soft metal pumps can be further subdivided into the Cu(I)/Ag(I)-translocating ATPases and the Zn(II)/Cd(II)/ Pb(II) ATPases (1).…”

Section: Discussionmentioning

confidence: 99%

Pb(II)-translocating P-type ATPases

Rensing

Sun

Mitra

et al. 1998

Journal of Biological Chemistry

182

169

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The cad operon of Staphylococcus aureus plasmid pI258, which confers cadmium resistance, encodes a transcriptional regulator, CadC, and CadA, an ATP-coupled Cd(II) pump that is a member of the superfamily of cation-translocating P-type ATPases. The Escherichia coli homologue of CadA, termed ZntA, is a Zn(II)/Cd(II) pump. The results described in this paper support the hypothesis that ZntA and CadA are Pb(II) pumps. First, CadC is a metal-responsive repressor that responds to soft metals in the order Pb>Cd>Zn. Second, both CadA and ZntA confer resistance to Pb(II). Third, transport of 65 Zn(II) in everted membrane vesicles of E. coli catalyzed by either of these two P-type ATPase superfamily members is inhibited by Pb(II).Exposure to environmental sources of lead is a serious public health concern. In humans chronic lead exposure produces neurotoxicity, anemia, and kidney damage, and acute lead toxicity can be fatal. Neither the specific lead transporters nor the regulatory elements that control the expression of the transporter genes have been identified. As models for human metal toxicity, we have been characterizing transporters for toxic metals and their genetic regulation (1, 2) and report here the identification of two P-type ATPases that are responsible for Pb(II) extrusion and resistance in bacteria.Bacterial metal ion resistance probably arose early in evolution due to widespread geological occurrence of metals. Bacterial cells have chromosomally and plasmid-encoded mechanisms for extrusion of antimicrobial substances, including toxic soft metals (3). While the ionic forms of some of these metals such as zinc and copper are essential for all organisms, all of these ions are toxic in excess. ZntA from Escherichia coli and CadA from plasmid pI258 of Staphylococcus aureus are both members of the superfamily of P-type cation-translocating ATPases but belong to a subgroup of soft metal transporters that includes CopA, a Cu(I) pump from Enterococcus hirae, and eukaryotic Cu(I) homeostasis proteins such as the Menkes and Wilson disease-associated proteins (1, 4, 5). ZntA has been shown to catalyze ATP-dependent transport of Zn(II) and Cd(II) (6), and CadA has been shown to transport Cd(II) (7). Both have been shown to confer resistance to cadmium and zinc ions (8 -10). The pI258 cadCA operon is regulated at the transcriptional level by the product of the cadC gene, which encodes the 122-residue CadC repressor (11-13).In this report, we show that CadC repression of the cad promoter is relieved upon addition of soft metals, with the order of effectiveness Pb(II) Ͼ Cd(II) Ͼ Zn(II). In E. coli Zn(II) responsiveness could be observed only in a zntA-disrupted strain. The zntA-disrupted strain of E. coli exhibited hypersensitivity to Pb(II) that was complemented by cadA, indicating that both soft metal-translocating P-type ATPases are essential for Pb(II) resistance in bacteria. Everted membrane vesicles from cells expressing either zntA or cadA exhibited ATPdependent 65 Zn(II) accumulation. Since no radioisotopes of ...

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Section: Discussionmentioning

confidence: 99%

Pb(II)-translocating P-type ATPases

Rensing

Sun

Mitra

et al. 1998

Journal of Biological Chemistry

182

169

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“…All of these genes are also in the pathway of iron and copper transport and regulation of heme during iron starvation. The CTR1 is a copper transporter and CCC2 gene is Cu 2+ -transporting P-type ATPase [21]. Thus, the highly induced processes under 56MESS treatment are the iron and copper uptake and homeostasis.…”

Section: Cytotoxicity Of 56mess In the Cisplatin-resistant L1210cisr mentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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“…Therefore, it is possible that copper is needed for both ethylene binding and functional receptors. RAN1 encodes a protein similar to the copper-transporting CPx class of P-type ATPases such as Ccc2 protein from Saccharomyces cerevisiae and human Menkes/Wilson proteins (31)(32)(33)(34)(35)(36). One function of these ATPases is to deliver copper to copper-containing enzymes in extracytoplasmic compartments.…”

mentioning

confidence: 99%

The Copper Transporter RAN1 Is Essential for Biogenesis of Ethylene Receptors in Arabidopsis

Binder

Rodrı́guez

Bleecker

2010

Journal of Biological Chemistry

120

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Plants utilize ethylene as a hormone to regulate multiple developmental processes and to coordinate responses to biotic and abiotic stress. In Arabidopsis thaliana, a small family of five receptor proteins typified by ETR1 mediates ethylene perception. Our previous work suggested that copper ions likely play a role in ethylene binding. An independent study indicated that the ran1 mutants, which display ethylene-like responses to the ethylene antagonist trans-cyclooctene, have mutations in the RAN1 copper-transporting P-type ATPase, once again linking copper ions to the ethylene-response pathway. The results presented herein indicate that genetically engineered Saccharomyces cerevisiae expressing ETR1 but lacking the RAN1 homolog Ccc2p (⌬ccc2) lacks ethylene-binding activity. Ethylene-binding activity was restored when copper ions were added to the ⌬ccc2 mutants, showing that it is the delivery of copper that is important. Additionally, transformation of the ⌬ccc2 mutant yeast with RAN1 rescued ethylene-binding activity. Analysis of plants carrying loss-of-function mutations in ran1 showed that they lacked ethylene-binding activity, whereas seedlings carrying weak alleles of ran1 had normal ethylene-binding activity but were hypersensitive to copper-chelating agents. Altogether, the results show an essential role for RAN1 in the biogenesis of the ethylene receptors and copper homeostasis in Arabidopsis seedlings. Furthermore, the results indicate cross-talk between the ethylene-response pathway and copper homeostasis in Arabidopsis seedling development.

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Sequence, mapping and disruption of CCC2, a gene that cross‐complements the Ca²⁺‐sensitive phenotype of csg1 mutants and encodes a P‐type ATPase belonging to the Cu²⁺‐ATPase subfamily

Cited by 163 publications

References 24 publications

Pb(II)-translocating P-type ATPases

Pb(II)-translocating P-type ATPases

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

The Copper Transporter RAN1 Is Essential for Biogenesis of Ethylene Receptors in Arabidopsis

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