Journal articles on the topic 'Copper responsive regulator'
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1
Peuser, Verena, Jens Glaeser, and Gabriele Klug. "The RSP_2889 gene product of Rhodobacter sphaeroides is a CueR homologue controlling copper-responsive genes." Microbiology 157, no. 12 (December 1, 2011): 3306–13. http://dx.doi.org/10.1099/mic.0.051607-0.
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Metal homeostasis is important in all living cells in order to provide sufficient amounts of metal ions for biological processes but to prevent toxic effects by excess amounts. Here we show that the gene product of RSP_2889 of the facultatively photosynthetic bacterium Rhodobacter sphaeroides is homologous to CueR, a regulator of copper metabolism in Escherichia coli and other bacteria. CueR binds to the promoter regions of genes for a copper-translocating ATPase and for a copper chaperone and is responsible for their high expression when cells are exposed to elevated levels of copper ions. While deletion of RSP_2889 has no significant effect on copper resistance, expression from a low-copy-number plasmid mediates increased sensitivity to copper.
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Ettema, Thijs J. G., Arie B. Brinkman, Packo P. Lamers, Noor G. Kornet, Willem M. de Vos, and John van der Oost. "Molecular characterization of a conserved archaeal copper resistance (cop) gene cluster and its copper-responsive regulator in Sulfolobus solfataricus P2." Microbiology 152, no. 7 (July 1, 2006): 1969–79. http://dx.doi.org/10.1099/mic.0.28724-0.
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Using a comparative genomics approach, a copper resistance gene cluster has been identified in multiple archaeal genomes. The cop cluster is predicted to encode a metallochaperone (CopM), a P-type copper-exporting ATPase (CopA) and a novel, archaea-specific transcriptional regulator (CopT) which might control the expression of the cop genes. Sequence analysis revealed that CopT has an N-terminal DNA-binding helix–turn–helix domain and a C-terminal TRASH domain; TRASH is a novel domain which has recently been proposed to be uniquely involved in metal-binding in sensors, transporters and trafficking proteins in prokaryotes. The present study describes the molecular characterization of the cop gene cluster in the thermoacidophilic crenarchaeon Sulfolobus solfataricus. The polycistronic copMA transcript was found to accumulate in response to growth-inhibiting copper concentrations, whereas copT transcript abundance appeared to be constitutive. DNA-binding assays revealed that CopT binds to the copMA promoter at multiple sites, both upstream and downstream of the predicted TATA-BRE site. Copper was found to specifically modulate the affinity of DNA binding by CopT. This study describes a copper-responsive operon in archaea, a new family of archaeal DNA-binding proteins, and supports the idea that this domain plays a prominent role in the archaeal copper response. A model is proposed for copper-responsive transcriptional regulation of the copMA gene cluster.
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Grosse-Siestrup, Benjamin T., Tuhina Gupta, Shelly Helms, Samantha L. Tucker, Martin I. Voskuil, Frederick D. Quinn, and Russell K. Karls. "A Role for Mycobacterium tuberculosis Sigma Factor C in Copper Nutritional Immunity." International Journal of Molecular Sciences 22, no. 4 (February 20, 2021): 2118. http://dx.doi.org/10.3390/ijms22042118.
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Sigma factor C (SigC) contributes to Mycobacterium tuberculosis virulence in various animal models, but the stress response coordinated by this transcription factor was undefined. The results presented here indicate that SigC prevents copper starvation. Whole genome expression studies demonstrate short-term (4-h) induction of sigC, controlled from a tetracycline-inducible promoter, upregulates ctpB and genes in the nonribosomal peptide synthase (nrp) operon. These genes are expressed at higher levels after 48-h sigC induction, but also elevated are genes encoding copper-responsive regulator RicR and RicR-regulated copper toxicity response operon genes rv0846–rv0850, suggesting prolonged sigC induction results in excessive copper uptake. No growth and global transcriptional differences are observed between a sigC null mutant relative to its parent strain in 7H9 medium. In a copper-deficient medium, however, growth of the sigC deletion strain lags the parent, and 40 genes (including those in the nrp operon) are differentially expressed. Copper supplementation reverses the growth defect and silences most transcriptional differences. Together, these data support SigC as a transcriptional regulator of copper acquisition when the metal is scarce. Attenuation of sigC mutants in severe combined immunodeficient mice is consistent with an inability to overcome innate host defenses that sequester copper ions to deprive invading microbes of this essential micronutrient.
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Young, Christie A., Lily D. Gordon, Zhong Fang, Robert C. Holder, and Sean D. Reid. "Copper Tolerance and Characterization of a Copper-Responsive Operon,copYAZ, in an M1T1 Clinical Strain of Streptococcus pyogenes." Journal of Bacteriology 197, no. 15 (May 26, 2015): 2580–92. http://dx.doi.org/10.1128/jb.00127-15.
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ABSTRACTInfection withStreptococcus pyogenesis associated with a breadth of clinical manifestations ranging from mild pharyngitis to severe necrotizing fasciitis. Elevated levels of intracellular copper are highly toxic to this bacterium, and thus, the microbe must tightly regulate the level of this metal ion by one or more mechanisms, which have, to date, not been clearly defined. In this study, we have identified two virulence mechanisms by whichS. pyogenesprotects itself against copper toxicity. We defined a set of putative genes,copY(for a regulator),copA(for a P1-type ATPase), andcopZ(for a copper chaperone), whose expression is regulated by copper. Our results indicate that these genes are highly conserved among a range of clinicalS. pyogenesisolates. ThecopY,copA, andcopZgenes are induced by copper and are transcribed as a single unit. Heterologous expression assays revealed thatS. pyogenesCopA can confer copper tolerance in a copper-sensitiveEscherichia colimutant by preventing the accumulation of toxic levels of copper, a finding that is consistent with a role for CopA in copper export. Evaluation of the effect of copper stress onS. pyogenesin a planktonic or biofilm state revealed that biofilms may aid in protection during initial exposure to copper. However, copper stress appears to prevent the shift from the planktonic to the biofilm state. Therefore, our results indicate thatS. pyogenesmay use several virulence mechanisms, including altered gene expression and a transition to and from planktonic and biofilm states, to promote survival during copper stress.IMPORTANCEBacterial pathogens encounter multiple stressors at the host-pathogen interface. This study evaluates a virulence mechanism(s) utilized byS. pyogenesto combat copper at sites of infection. A better understanding of pathogen tolerance to stressors such as copper is necessary to determine how host-pathogen interactions impact bacterial survival during infections. These insights may lead to the identification of novel therapeutic targets that can be used to address antibiotic resistance.
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Quinn, Jeanette M., Janette Kropat, and Sabeeha Merchant. "Copper Response Element and Crr1-Dependent Ni2+-Responsive Promoter for Induced, Reversible Gene Expression in Chlamydomonas reinhardtii." Eukaryotic Cell 2, no. 5 (October 2003): 995–1002. http://dx.doi.org/10.1128/ec.2.5.995-1002.2003.
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ABSTRACT The Cpx1 and Cyc6 genes of Chlamydomonas reinhardtii are activated in copper-deficient cells via a signal transduction pathway that requires copper response elements (CuREs) and a copper response regulator defined by the CRR1 locus. The two genes can also be activated by provision of nickel or cobalt ions in the medium. The response to nickel ions requires at least one CuRE and also CRR1 function, suggesting that nickel interferes with a component in the nutritional copper signal transduction pathway. Nickel does not act by preventing copper uptake/utilization because (i) holoplastocyanin formation is unaffected in Ni2+-treated cells and (ii) provision of excess copper cannot reverse the Ni-dependent activation of the target genes. The CuRE is sufficient for conferring Ni-responsive expression to a reporter gene, which suggests that the system has practical application as a vehicle for inducible gene expression. The inducer can be removed either by replacing the medium or by chelating the inducer with excess EDTA, either of which treatments reverses the activation of the target genes.
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Olaya-Abril, Alfonso, Víctor M. Luque-Almagro, Jesús Hidalgo-Carrillo, Eduardo Chicano-Gálvez, Francisco J. Urbano, Conrado Moreno-Vivián, David J. Richardson, and María Dolores Roldán. "The NtrYX Two-Component System of Paracoccus denitrificans Is Required for the Maintenance of Cellular Iron Homeostasis and for a Complete Denitrification under Iron-Limited Conditions." International Journal of Molecular Sciences 23, no. 16 (August 15, 2022): 9172. http://dx.doi.org/10.3390/ijms23169172.
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Denitrification consists of the sequential reduction of nitrate to nitrite, nitric oxide, nitrous oxide, and dinitrogen. Nitrous oxide escapes to the atmosphere, depending on copper availability and other environmental factors. Iron is also a key element because many proteins involved in denitrification contain iron-sulfur or heme centers. The NtrYX two-component regulatory system mediates the responses in a variety of metabolic processes, including denitrification. A quantitative proteomic analysis of a Paracoccus denitrificans NtrY mutant grown under denitrifying conditions revealed the induction of different TonB-dependent siderophore transporters and proteins related to iron homeostasis. This mutant showed lower intracellular iron content than the wild-type strain, and a reduced growth under denitrifying conditions in iron-limited media. Under iron-rich conditions, it releases higher concentrations of siderophores and displayes lower nitrous oxide reductase (NosZ) activity than the wild-type, thus leading to nitrous oxide emission. Bioinformatic and qRT-PCR analyses revealed that NtrYX is a global transcriptional regulatory system that responds to iron starvation and, in turn, controls expression of the iron-responsive regulators fur, rirA, and iscR, the denitrification regulators fnrP and narR, the nitric oxide-responsive regulator nnrS, and a wide set of genes, including the cd1-nitrite reductase NirS, nitrate/nitrite transporters and energy electron transport proteins.
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Upadhyay, Srijana, Guadalupe Torres, and Xiaorong Lin. "Laccases Involved in 1,8-Dihydroxynaphthalene Melanin Biosynthesis in Aspergillus fumigatus Are Regulated by Developmental Factors and Copper Homeostasis." Eukaryotic Cell 12, no. 12 (October 11, 2013): 1641–52. http://dx.doi.org/10.1128/ec.00217-13.
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ABSTRACTAspergillus fumigatusproduces heavily melanized infectious conidia. The conidial melanin is associated with fungal virulence and resistance to various environmental stresses. This 1,8-dihydroxynaphthalene (DHN) melanin is synthesized by enzymes encoded in a gene cluster inA. fumigatus, including two laccases, Abr1 and Abr2. Although this gene cluster is not conserved in all aspergilli, laccases are critical for melanization in all species examined. Here we show that the expression ofA. fumigatuslaccases Abr1/2 is upregulated upon hyphal competency and drastically increased during conidiation. The Abr1 protein is localized at the surface of stalks and conidiophores, but not in young hyphae, consistent with the gene expression pattern and its predicted role. The induction of Abr1/2 upon hyphal competency is controlled by BrlA, the master regulator of conidiophore development, and is responsive to the copper level in the medium. We identified a developmentally regulated putative copper transporter, CtpA, and found that CtpA is critical for conidial melanization under copper-limiting conditions. Accordingly, disruption of CtpA enhanced the induction ofabr1andabr2, a response similar to that induced by copper starvation. Furthermore, nonpigmentedctpAΔ conidia elicited much stronger immune responses from the infected invertebrate hostGalleria mellonellathan the pigmentedctpAΔ or wild-type conidia. Such enhancement in elicitingGalleriaimmune responses was independent of thectpAΔ conidial viability, as previously observed for the DHN melanin mutants. Taken together, our findings indicate that both copper homeostasis and developmental regulators control melanin biosynthesis, which affects conidial surface properties that shape the interaction between this pathogen and its host.
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Raghunandanan, Sajith, Ranjit Ramachandran, Roshna Lawrence Gomez, Sivasankar Devanarayanan, Akhila Bommakanti, Anand Kumar Kondapi, Raghavan Varadarajan, and Ramakrishnan Ajay Kumar. "Rv0474 is a copper‐responsive transcriptional regulator that negatively regulates expression of RNA polymerase β subunit in Mycobacterium tuberculosis." FEBS Journal 285, no. 20 (September 5, 2018): 3849–69. http://dx.doi.org/10.1111/febs.14637.
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van Vliet, Arnoud H. M., Ernst J. Kuipers, Barbara Waidner, Beverly J. Davies, Nicolette de Vries, Charles W. Penn, Christina M. J. E. Vandenbroucke-Grauls, Manfred Kist, Stefan Bereswill, and Johannes G. Kusters. "Nickel-Responsive Induction of Urease Expression inHelicobacter pylori Is Mediated at the Transcriptional Level." Infection and Immunity 69, no. 8 (August 1, 2001): 4891–97. http://dx.doi.org/10.1128/iai.69.8.4891-4897.2001.
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ABSTRACT The nickel-containing enzyme urease is an essential colonization factor of the gastric pathogen Helicobacter pylori, as it allows the bacterium to survive the acidic conditions in the gastric mucosa. Although urease can represents up to 10% of the total protein content of H. pylori, expression of urease genes is thought to be constitutive. Here it is demonstrated that H. pyloriregulates the expression and activity of its urease enzyme as a function of the availability of the cofactor nickel. Supplementation of brucella growth medium with 1 or 100 μM NiCl2 resulted in up to 3.5-fold-increased expression of the urease subunit proteins UreA and UreB and up to 12-fold-increased urease enzyme activity. The induction was specific for nickel, since the addition of cadmium, cobalt, copper, iron, manganese, or zinc did not affect the expression of urease. Both Northern hybridization studies and a transcriptionalureA::lacZ fusion demonstrated that the observed nickel-responsive regulation of urease is mediated at the transcriptional level. Mutation of the HP1027 gene, encoding the ferric uptake regulator (Fur), did not affect the expression of urease in unsupplemented medium but reduced the nickel induction of urease expression to only twofold. This indicates that Fur is involved in the modulation of urease expression in response to nickel. These data demonstrate nickel-responsive regulation of H. pyloriurease, a phenomenon likely to be of importance during the colonization and persistence of H. pylori in the gastric mucosa.
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Karmacharya, Jayram, Prasansah Shrestha, So-Ra Han, Hyun Park, and Tae-Jin Oh. "Complete Genome Sequencing of Polar Arthrobacter sp. PAMC25284, Copper Tolerance Potential Unraveled with Genomic Analysis." International Journal of Microbiology 2022 (August 25, 2022): 1–12. http://dx.doi.org/10.1155/2022/1162938.
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The genus Arthrobacter is a known group of Gram-positive, opportunistic pathogenic bacteria from cold climates, with members that are believed to play a variety of roles at low temperatures. However, their survival mechanisms in frigid environments like the Antarctic are still unknown. We identified a species of Arthrobacter isolated from seawater in the polar region using 16S rRNA sequence analysis. The strain PAMC25284 genome consists of a circular chromosome with a GC content of 65.6% and is projected to contain 3,588 genes, of which 3,150 are protein coding, 366 are pseudogenes, 19 are rRNA coding, and 50 are tRNA coding genes. Using comparative genomics, we showed that PMAC25284 has copper-transporting ATPases, copper chaperone, copper-responsive transcriptional regulator, and multi-copper oxidase domains, which are found in both Gram-positive (like Mycobacterium tuberculosis and Enterococcus hirae) and Gram-negative bacteria (like E. coli and Pseudomonas aeruginosa). The existence of 4 multi-copper oxidase genes, which supplied an additional copper defense mechanism, could be intriguing information regarding Gram-positive bacteria such as Arthrobacter sp. PAMC25284. In addition, our strain PAMC25284 has the same MmcO gene as M. tuberculosis, with a locus tag KY499_RS04055 similarity of 40.61%, which is the highest among the Gram-positive and Gram-negative bacteria studied for this gene. Our cold-adapted Arthrobacter sp. strain PAMC25564 was published previously but did not contain a multi-copper oxidase domain-containing gene, but strain PAMC25284 was studied in this study.
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Egli, Dieter, Hasmik Yepiskoposyan, Anand Selvaraj, Kuppusamy Balamurugan, Rama Rajaram, Andreas Simons, Gerd Multhaup, et al. "A Family Knockout of All Four Drosophila Metallothioneins Reveals a Central Role in Copper Homeostasis and Detoxification." Molecular and Cellular Biology 26, no. 6 (March 15, 2006): 2286–96. http://dx.doi.org/10.1128/mcb.26.6.2286-2296.2006.
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ABSTRACT Metallothioneins are ubiquitous, small, cysteine-rich proteins with the ability to bind heavy metals. In spite of their biochemical characterization, their in vivo function remains elusive. Here, we report the generation of a metallothionein gene family knockout in Drosophila melanogaster by targeted disruption of all four genes (MtnA to -D). These flies are viable if raised in standard laboratory food. During development, however, they are highly sensitive to copper, cadmium, and (to a lesser extent) zinc load. Metallothionein expression is particularly important for male viability; while copper load during development affects males and females equally, adult males lacking metallothioneins display a severely reduced life span, possibly due to copper-mediated oxidative stress. Using various reporter gene constructs, we find that different metallothioneins are expressed with virtually the same tissue specificity in larvae, notably in the intestinal tract at sites of metal accumulation, including the midgut's “copper cells.” The same expression pattern is observed with a synthetic minipromoter consisting only of four tandem metal response elements. From these and other experiments, we conclude that tissue specificity of metallothionein expression is a consequence, rather than a cause, of metal distribution in the organism. The bright orange luminescence of copper accumulated in copper cells of the midgut is severely reduced in the metallothionein gene family knockout, as well as in mutants of metal-responsive transcription factor 1 (MTF-1), the main regulator of metallothionein expression. This indicates that an in vivo metallothionein-copper complex forms the basis of this luminescence. Strikingly, metallothionein mutants show an increased, MTF-1-dependent induction of metallothionein promoters in response to copper, cadmium, silver, zinc, and mercury. We conclude that free metal, but not metallothionein-bound metal, triggers the activation of MTF-1 and that metallothioneins regulate their own expression by a negative feedback loop.
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Thai Huyen, Pham Ngoc, Hoang Thi Lan Xuan, Nguyen Nguyen Chuong, and Nguyen Phuong Thao. "Expression study of stress-related genes in salinity-treated transgenic Arabidopsis harboring soybean Response Regulator 34." Vietnam Journal of Biotechnology 20, no. 2 (June 30, 2022): 289–96. http://dx.doi.org/10.15625/1811-4989/16149.
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Owing to their sessile nature, plants are easily affected by various extenal factors. Among those, drought and salinity are considered as the most common stresses, which often pose a threat to plant growth and development. Major effects of the drought and salinity are interconnected and drive similar series of molecular changes in plants. These alterations in response to the stress are under the regulation of various signaling pathways, including the engangement of evolutionarily conserved two-component systems (TCSs). Three components with distinct functions can be found in a functional TCS, which are histidine kinases (HKs), histidine-containing phosphotransfer proteins (HPts), and response regulator proteins (RRs). Previous research revealed that the soybean (Glycine max) GmRR34 acts as an important regulatory protein in plants under drought stress conditions. In this project, the investigation on the role of GmRR34 in osmotic stress responses was extended to salinity by examining the expression of a subset of salinity-responsive genes using RT-qPCR method. Our analyses showed that the transgenic Arabidopsis plants ectopically expressing GmRR34 displayed enhanced expression of several important stress-related genes, including Catalase 1 (CAT1), Stromal ascorbate peroxidase 1 (sAPX1), Copper/zinc superoxide dismutase 1 (CSD1), Sodium/hydrogen exchanger 1 (NHX1) and Salt overly sensitive 2 (SOS2). These results indicate that GmRR34-transgenic plants might be more salt-tolerant thanks to stronger activities of antioxidant enzymes and better capacity in maintaining cytosolic ion homeostasis. Therefore, it is highlighted the necessity to perform further studies to fully characterize the GmRR34 biological functions as well as explore its application potential in enhancing the salt tolerance of crop plants.
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Martell, Danya J., Chandra P. Joshi, Ahmed Gaballa, Ace George Santiago, Tai-Yen Chen, Won Jung, John D. Helmann, and Peng Chen. "Metalloregulator CueR biases RNA polymerase’s kinetic sampling of dead-end or open complex to repress or activate transcription." Proceedings of the National Academy of Sciences 112, no. 44 (October 19, 2015): 13467–72. http://dx.doi.org/10.1073/pnas.1515231112.
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Metalloregulators respond to metal ions to regulate transcription of metal homeostasis genes. MerR-family metalloregulators act on σ70-dependent suboptimal promoters and operate via a unique DNA distortion mechanism in which both the apo and holo forms of the regulators bind tightly to their operator sequence, distorting DNA structure and leading to transcription repression or activation, respectively. It remains unclear how these metalloregulator−DNA interactions are coupled dynamically to RNA polymerase (RNAP) interactions with DNA for transcription regulation. Using single-molecule FRET, we study how the copper efflux regulator (CueR)—a Cu+-responsive MerR-family metalloregulator—modulates RNAP interactions with CueR’s cognate suboptimal promoter PcopA, and how RNAP affects CueR−PcopAinteractions. We find that RNAP can form two noninterconverting complexes at PcopAin the absence of nucleotides: a dead-end complex and an open complex, constituting a branched interaction pathway that is distinct from the linear pathway prevalent for transcription initiation at optimal promoters. Capitalizing on this branched pathway, CueR operates via a “biased sampling” instead of “dynamic equilibrium shifting” mechanism in regulating transcription initiation; it modulates RNAP’s binding–unbinding kinetics, without allowing interconversions between the dead-end and open complexes. Instead, the apo-repressor form reinforces the dominance of the dead-end complex to repress transcription, and the holo-activator form shifts the interactions toward the open complex to activate transcription. RNAP, in turn, locks CueR binding at PcopAinto its specific binding mode, likely helping amplify the differences between apo- and holo-CueR in imposing DNA structural changes. Therefore, RNAP and CueR work synergistically in regulating transcription.
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Li, Zhefei, Xiuyong Song, Juanjuan Wang, Xiaoli Bai, Engting Gao, and Gehong Wei. "Nickel and cobalt resistance properties of Sinorhizobium meliloti isolated from Medicago lupulina growing in gold mine tailing." PeerJ 6 (July 10, 2018): e5202. http://dx.doi.org/10.7717/peerj.5202.
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Sinorhizobium meliloti CCNWSX0020, isolated from root nodules of Medicago lupulina growing in gold mine tailings in the northwest of China, displayed multiple heavy metal resistance and growth promotion of M. lupulina. In our previous work, the expression level of dmeR and dmeF genes were induced by Cu2+ through comparative transcriptome approach. Based on protein analysis, the dmeF encoded for a protein which showed a 37% similarity to the cation transporter DmeF of Cupriavidus metallidurans, whereas dmeR encoded transcriptional regulator which was highly homologous with DmeR belonging to RcnR/CsoR family metal-responsive transcriptional regulator. In addition to copper, quantitative real-time PCR analysis showed that dmeR and dmeF were also induced by nickel and cobalt. To investigate the functions of dmeR and dmeF in S. meliloti CCNWSX0020, the dmeR and dmeF deletion mutants were constructed. The dmeF mutant was more sensitive to Co2 + and Ni2 + than the wild type strain. Pot experiments were carried out to determine whether the growth of M. lupulina was affected when the dmeF gene was knocked out in the presence of nickel or cobalt. Results indicated that the nodule number of the host plant inoculated with the dmeF deletion mutant was significantly less than the S. meliloti CCNWSX0020 wild-type in the presence of Co2 + or Ni2 +. However, when standardized by nodule fresh weight, the nitrogenase activities of nodules infected by the dmeF deletion mutant was similar to nitrogenase activity of the wild type nodule.
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Joshi, Chandra P., Debashis Panda, Danya J. Martell, Nesha May Andoy, Tai-Yen Chen, Ahmed Gaballa, John D. Helmann, and Peng Chen. "Direct substitution and assisted dissociation pathways for turning off transcription by a MerR-family metalloregulator." Proceedings of the National Academy of Sciences 109, no. 38 (September 4, 2012): 15121–26. http://dx.doi.org/10.1073/pnas.1208508109.
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Metalloregulators regulate transcription in response to metal ions. Many studies have provided insights into how transcription is activated upon metal binding by MerR-family metalloregulators. In contrast, how transcription is turned off after activation is unclear. Turning off transcription promptly is important, however, as the cells would not want to continue expressing metal resistance genes and thus waste energy after metal stress is relieved. Using single-molecule FRET measurements we studied the dynamic interactions of the copper efflux regulator (CueR), a Cu+-responsive MerR-family metalloregulator, with DNA. Besides quantifying its DNA binding and unbinding kinetics, we discovered that CueR spontaneously flips its binding orientation at the recognition site. CueR also has two different binding modes, corresponding to interactions with specific and nonspecific DNA sequences, which would facilitate recognition localization. Most strikingly, a CueR molecule coming from solution can directly substitute for a DNA-bound CueR or assist the dissociation of the incumbent CueR, both of which are unique examples for any DNA-binding protein. The kinetics of the direct protein substitution and assisted dissociation reactions indicate that these two unique processes can provide efficient pathways to replace a DNA-bound holo-CueR with apo-CueR, thus turning off transcription promptly and facilely.
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Sullivan, Matthew J., Kelvin G. K. Goh, and Glen C. Ulett. "Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus." PLOS Pathogens 18, no. 7 (July 21, 2022): e1010607. http://dx.doi.org/10.1371/journal.ppat.1010607.
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Metals such as copper (Cu) and zinc (Zn) are important trace elements that can affect bacterial cell physiology but can also intoxicate bacteria at high concentrations. Discrete genetic systems for management of Cu and Zn efflux have been described in several bacteria pathogens, including streptococci. However, insight into molecular cross-talk between systems for Cu and Zn management in bacteria that drive metal detoxification, is limited. Here, we describe a biologically consequential cross-system effect of metal management in group B Streptococcus (GBS) governed by the Cu-responsive copY regulator in response to Zn. RNAseq analysis of wild-type (WT) and copY-deficient GBS subjected to metal stress revealed unique transcriptional links between the systems for Cu and Zn detoxification. We show that the Cu-sensing role of CopY extends beyond Cu and enables CopY to regulate Cu and Zn stress responses that effect changes in gene function for central cellular processes, including riboflavin synthesis. CopY also supported GBS intracellular survival in human macrophages and virulence during disseminated infection in mice. In addition, we show a novel role for CovR in modulating GBS resistance to Zn intoxication. Identification of the Zn resistome of GBS using TraDIS revealed a suite of genes essential for GBS growth in metal stress. Several of the genes identified are novel to systems that support bacterial survival in metal stress and represent a diverse set of mechanisms that underpin microbial metal homeostasis during cell stress. Overall, this study reveals a new and important mechanism of cross-system complexity driven by CopY in bacteria to regulate cellular management of metal stress and survival.
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Cantini, Francesca, Lucia Banci, and Marc Solioz. "The copper-responsive repressor CopR of Lactococcus lactis is a ‘winged helix’ protein." Biochemical Journal 417, no. 2 (December 23, 2008): 493–99. http://dx.doi.org/10.1042/bj20081713.
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CopR of Lactococcus lactis is a copper-responsive repressor involved in copper homoeostasis. It controls the expression of a total of 11 genes, the CopR regulon, in a copper-dependent manner. In the absence of copper, CopR binds to the promoters of the CopR regulon. Copper releases CopR from the promoters, allowing transcription of the downstream genes to proceed. CopR binds through its N-terminal domain to a ‘cop box’ of consensus TACANNTGTA, which is conserved in Firmicutes. We have solved the NMR solution structure of the N-terminal DNA-binding domain of CopR. The protein fold has a winged helix structure resembling that of the BlaI repressor which regulates antibiotic resistance in Bacillus licheniformis. CopR differs from other copper-responsive repressors, and the present structure represents a novel family of copper regulators, which we propose to call the CopY family.
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Beaudoin, Jude, Raphaël Ioannoni, Stéphane Mailloux, Samuel Plante, and Simon Labbé. "Transcriptional Regulation of the Copper Transporter Mfc1 in Meiotic Cells." Eukaryotic Cell 12, no. 4 (February 8, 2013): 575–90. http://dx.doi.org/10.1128/ec.00019-13.
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ABSTRACT Mfc1 is a meiosis-specific protein that mediates copper transport during the meiotic program in Schizosaccharomyces pombe . Although the mfc1 + gene is induced at the transcriptional level in response to copper deprivation, the molecular determinants that are required for its copper starvation-dependent induction are unknown. Promoter deletion and site-directed mutagenesis have allowed identification of a new cis -regulatory element in the promoter region of the mfc1 + gene. This cis -acting regulatory sequence containing the sequence TCGGCG is responsible for transcriptional activation of mfc1 + under low-copper conditions. The TCGGCG sequence contains a CGG triplet known to serve as a binding site for members of the Zn (2) Cys (6) binuclear cluster transcriptional regulator family. In agreement with this fact, one member of this group of regulators, denoted Mca1, was found to be required for maximum induction of mfc1 + gene expression. Analysis of Mca1 cellular distribution during meiosis revealed that it colocalizes with both chromosomes and sister chromatids during early, middle, and late phases of the meiotic program. Cells lacking Mca1 exhibited a meiotic arrest at metaphase I under low-copper conditions. Binding studies revealed that the N-terminal 150-residue segment of Mca1 expressed as a fusion protein in Escherichia coli specifically interacts with the TCGGCG sequence of the mfc1 + promoter. Taken together, these results identify the cis -regulatory TCGGCG sequence and the transcription factor Mca1 as critical components for activation of the meiotic copper transport mfc1 + gene in response to copper starvation.
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Raffa, Nicholas, Nir Osherov, and Nancy P. Keller. "Copper Utilization, Regulation, and Acquisition by Aspergillus fumigatus." International Journal of Molecular Sciences 20, no. 8 (April 23, 2019): 1980. http://dx.doi.org/10.3390/ijms20081980.
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Copper is an essential micronutrient for the opportunistic human pathogen, Aspergillus fumigatus. Maintaining copper homeostasis is critical for survival and pathogenesis. Copper-responsive transcription factors, AceA and MacA, coordinate a complex network responsible for responding to copper in the environment and determining which response is necessary to maintain homeostasis. For example, A. fumigatus uses copper exporters to mitigate the toxic effects of copper while simultaneously encoding copper importers and small molecules to ensure proper supply of the metal for copper-dependent processes such a nitrogen acquisition and respiration. Small molecules called isocyanides recently found to be produced by A. fumigatus may bind copper and partake in copper homeostasis similarly to isocyanide copper chelators in bacteria. Considering that the host uses copper as a microbial toxin and copper availability fluctuates in various environmental niches, understanding how A. fumigatus maintains copper homeostasis will give insights into mechanisms that facilitate the development of invasive aspergillosis and its survival in nature.
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Gaballa, Ahmed, Min Cao, and John D. Helmann. "Two MerR homologues that affect copper induction of the Bacillus subtilis copZA operon." Microbiology 149, no. 12 (December 1, 2003): 3413–21. http://dx.doi.org/10.1099/mic.0.26225-0.
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Copper ions induce expression of the Bacillus subtilis copZA operon encoding a metallochaperone, CopZ, and a CPx-type ATPase efflux protein, CopA. The copZA promoter region contains an inverted repeat sequence similar to that recognized by the mercury-sensing MerR protein. To investigate the possible involvement of MerR homologues in copZA regulation, null mutations were engineered affecting each of four putative MerR-type regulators: yyaN, yraB, yfmP and yhdQ. Two of these genes affected copper regulation. Mutation of yhdQ (hereafter renamed cueR) dramatically reduced copper induction of copZA, and purified CueR bound with high affinity to the copZA promoter region. These results suggest that CueR is a direct regulator of copZA transcription that mediates copper induction. Surprisingly, a yfmP mutation also reduced copper induction of copZA. Sequence analysis suggested that yfmP was cotranscribed with yfmO, encoding a putative multidrug efflux protein. The yfmPO operon is autoregulated: a yfmP mutation derepressed the yfmP promoter and purified YfmP bound the yfmP promoter region, but not the copZA promoter region. Since the yfmP mutant strain was predicted to express elevated levels of the YfmO efflux pump, it was hypothesized that copper efflux might be responsible for the reduced copZA induction. Consistent with this model, in a yfmP yfmO double mutant copper induction of copZA was normal. The results demonstrate the direct regulation of the B. subtilis copper efflux system by CueR, and indirect regulation by a putative multidrug efflux system.
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Virieux-Petit, Maxine, Florence Hammer-Dedet, Fabien Aujoulat, Estelle Jumas-Bilak, and Sara Romano-Bertrand. "From Copper Tolerance to Resistance in Pseudomonas aeruginosa towards Patho-Adaptation and Hospital Success." Genes 13, no. 2 (February 4, 2022): 301. http://dx.doi.org/10.3390/genes13020301.
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The hospital environment constitutes a reservoir of opportunistic pathogens responsible for healthcare-associated infections (HCAI) such as Pseudomonas aeruginosa (Pa). Pa persistence within technological niches, the increasing emergence of epidemic high-risk clones in HCAI, the epidemiological link between plumbing strains and clinical strains, make it a major nosocomial pathogen. Therefore, understanding the mechanisms of Pa adaptation to hospital water systems would be useful in preventing HCAI. This review deciphers how copper resistance contributes to Pa adaptation and persistence in a hospital environment, especially within copper water systems, and ultimately to its success as a causative agent of HCAI. Numerous factors are involved in copper homeostasis in Pa, among which active efflux conferring copper tolerance, and copper-binding proteins regulating the copper compartmentalization between periplasm and cytoplasm. The functional harmony of copper homeostasis is regulated by several transcriptional regulators. The genomic island GI-7 appeared as especially responsible for the copper resistance in Pa. Mechanisms of copper and antibiotic cross-resistance and co-resistance are also identified, with potential co-regulation processes between them. Finally, copper resistance of Pa confers selective advantages in colonizing and persisting in hospital environments but also appears as an asset at the host/pathogen interface that helps in HCAI occurrence.
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Cui, Yaya, Asita Chatterjee, Hailian Yang, and Arun K. Chatterjee. "Regulatory Network Controlling Extracellular Proteins in Erwinia carotovora subsp. carotovora: FlhDC, the Master Regulator of Flagellar Genes, Activates rsmB Regulatory RNA Production by Affecting gacA and hexA (lrhA) Expression." Journal of Bacteriology 190, no. 13 (April 25, 2008): 4610–23. http://dx.doi.org/10.1128/jb.01828-07.
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ABSTRACT Erwinia carotovora subsp. carotovora produces an array of extracellular proteins (i.e., exoproteins), including plant cell wall-degrading enzymes and Harpin, an effector responsible for eliciting hypersensitive reaction. Exoprotein genes are coregulated by the quorum-sensing signal, N-acyl homoserine lactone, plant signals, an assortment of transcriptional factors/regulators (GacS/A, ExpR1, ExpR2, KdgR, RpoS, HexA, and RsmC) and posttranscriptional regulators (RsmA, rsmB RNA). rsmB RNA production is positively regulated by GacS/A, a two-component system, and negatively regulated by HexA (PecT in Erwinia chrysanthemi; LrhA [LysR homolog A] in Escherichia coli) and RsmC, a putative transcriptional adaptor. While free RsmA, an RNA-binding protein, promotes decay of mRNAs of exoprotein genes, binding of RsmA with rsmB RNA neutralizes the RsmA effect. In the course of studies of GacA regulation, we discovered that a locus bearing strong homology to the flhDC operon of E. coli also controls extracellular enzyme production. A transposon insertion FlhDC− mutant produces very low levels of pectate lyase, polygalacturonase, cellulase, protease, and E. carotovora subsp. carotovora Harpin (HarpinEcc) and is severely attenuated in its plant virulence. The production of these exoproteins is restored in the mutant carrying an FlhDC+ plasmid. Sequence analysis and transcript assays disclosed that the flhD operon of E. carotovora subsp. carotovora, like those of other enterobacteria, consists of flhD and flhC. Complementation analysis revealed that the regulatory effect requires functions of both flhD and flhC products. The data presented here show that FlhDC positively regulates gacA, rsmC, and fliA and negatively regulates hexA (lrhA). Evidence shows that FlhDC controls extracellular protein production through cumulative effects on hexA and gacA. Reduced levels of GacA and elevated levels of HexA in the FlhDC− mutant are responsible for the inhibition of rsmB RNA production, a condition conducive to the accumulation of free RsmA. Indeed, studies with an RsmA− FlhDC− double mutant and multiple copies of rsmB + DNA establish that the negative effect of FlhDC deficiency is exerted via RsmA. The FlhDC-mediated regulation of fliA has no bearing on exoprotein production in E. carotovora subsp. carotovora. Our observations for the first time establish a regulatory connection between FlhDC, HexA, GacA, and rsmB RNA in the context of the exoprotein production and virulence of E. carotovora subsp. carotovora.
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Rademacher, Corinna, and Bernd Masepohl. "Copper-responsive gene regulation in bacteria." Microbiology 158, no. 10 (October 1, 2012): 2451–64. http://dx.doi.org/10.1099/mic.0.058487-0.
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Munson, George P., Deborah L. Lam, F. Wayne Outten, and Thomas V. O'Halloran. "Identification of a Copper-Responsive Two-Component System on the Chromosome of Escherichia coli K-12." Journal of Bacteriology 182, no. 20 (October 15, 2000): 5864–71. http://dx.doi.org/10.1128/jb.182.20.5864-5871.2000.
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ABSTRACT Using a genetic screen we have identified two chromosomal genes,cusRS (ylcA ybcZ), from Escherichia coli K-12 that encode a two-component, signal transduction system that is responsive to copper ions. This regulatory system is required for copper-induced expression of pcoE, a plasmid-borne gene from the E. coli copper resistance operon pco. The closest homologs of CusR and CusS are plasmid-borne two-component systems that are also involved in metal responsive gene regulation: PcoR and PcoS from the pcooperon of E. coli; CopR and CopS from thecop operon, which provides copper resistance toPseudomonas syringae; and SilR and SilS from thesil locus, which provides silver ion resistance toSalmonella enterica serovar Typhimurium. The genescusRS are also required for the copper-dependent expression of at least one chromosomal gene, designated cusC(ylcB), which is allelic to the recently identified virulence gene ibeB in E. coli K1. Thecus locus may comprise a copper ion efflux system, because the expression of cusC is induced by high concentrations of copper ions. Furthermore, the translation products of cusCand additional downstream genes are homologous to known metal ion antiporters.
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Dilworth, M. J., J. G. Howieson, W. G. Reeve, R. P. Tiwari, and A. R. Glenn. "Acid tolerance in legume root nodule bacteria and selecting for it." Australian Journal of Experimental Agriculture 41, no. 3 (2001): 435. http://dx.doi.org/10.1071/ea99155.
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Bacteria face a variety of problems in trying to survive and grow in acidic environments. These include maintaining intracellular pH (pHi) in order to protect internal cell components, modifying or abandoning those external structures inevitably exposed to acidity, and resisting stresses whose interaction with pH may be the actual determinant of survival or growth rather than H+ toxicity per se. An important aspect of acid resistance in Gram-negative bacteria (including the root nodule bacteria) is the adaptive acid tolerance response (ATR), whereby cells grown at moderately acid pH are much more resistant to being killed under strongly acidic conditions than are cells grown at neutral pH. Survival during pH shock is also markedly affected by the calcium concentration in the medium. The pH at which commercial legume inoculants are grown and supplied for inoculation into acid soils may therefore be of considerable importance for initial inoculant survival. The mechanisms of resistance to acidity in root nodule bacteria have been investigated via 3 approaches: (i) creation of acid-sensitive mutants from acid-tolerant strains, and identification of the genes involved; (ii) random insertion of reporter genes to create mutants with pH-dependent reporter expression; and (iii) proteomics and identification of proteins regulated in response to acidity. The results of the first approach, directed at genes essential for growth at acid pH, have identified a sensor–regulator gene pair (actS–actR), a copper-transporting ATPase (actP), and another gene involved in lipid metabolism (actA), inactivation of which results in sensitivity to heavy metals. While the ActS–ActR system is undoubtedly required for both acid tolerance and the ATR, it is also involved in global regulation of a wide range of cellular processes. The second approach has allowed identification of a range of acid-responsive genes, which are not themselves critical to growth at low pH. One of these (phrR) is itself a regulator gene induced by a range of stresses including acid pH, but not controlled by the ActS–ActR system. Another, lpiA, responds specifically to acidity (not to other stresses) and may well be an antiporter related to nhaB, which is involved in Na+ transport in other bacteria. The third approach indicates a number of proteins whose concentration changes with a switch from neutral to acidic growth pH; most of these seem to have no homologues in the protein databases, while the blocked N-terminal sequences of others have prevented identification. It has been common experience that strains of root nodule bacteria selected for acid tolerance in the laboratory are not necessarily successful as inoculants in acid soils. In the light of the complex interactive effects on growth and survival of H+, Ca2+ and Cu2+ concentrations in our studies, this lack of correlation is no longer surprising. It remains to be seen whether it will be possible to improve the correlation between growth on laboratory media and performance in acid soils by determining which strains show an ATR, and by screening on media with defined ranges of concentration of some of these critical metal ions, perhaps approximating those to be expected in the soils in question.
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Das, Dola, Nisha Tapryal, Shyamal K. Goswami, Paul L. Fox, and Chinmay K. Mukhopadhyay. "Regulation of ceruloplasmin in human hepatic cells by redox active copper: identification of a novel AP-1 site in the ceruloplasmin gene." Biochemical Journal 402, no. 1 (January 25, 2007): 135–41. http://dx.doi.org/10.1042/bj20060963.
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Cp (ceruloplasmin), a copper containing plasma protein, mainly synthesized in the liver, is known to be functional between the interface of iron and copper metabolism. We have reported previously that Cp is regulated by cellular iron status, but the process of the regulation of Cp by copper still remains a subject for investigation. In the present paper, we show that PDTC (pyrrolidine dithiocarbamate), a thiol compound widely known to increase intracellular redox copper, regulates Cp expression in hepatic cells by a copper-dependent transcriptional mechanism. To find out the mechanism of induction, chimeric constructs of the Cp 5′-flanking region driving luciferase were transfected into human hepatic cells. Deletion and mutational analyses showed the requirement of a novel APRE [AP-1 (activator protein-1) responsive element] present about 3.7 kb upstream of the translation initiation site. The role of AP-1 was confirmed by electrophoretic mobility-shift analysis. Western blot and overexpression studies detected the AP-1 as a heterodimer of c-jun and c-fos proteins. The activation of AP-1 was found to be copper-dependent as a specific extracellular chelator bathocuproine disulfonic acid blocked PDTC-mediated induction of AP-1–DNA binding and increased reporter gene activity. Whereas, in a copper-free medium, PDTC failed to activate either AP-1 or Cp synthesis, supplementation of copper could reverse AP-1 activation and Cp synthesis. Our finding is not only the first demonstration of regulation of Cp by redox copper but may also explain previous findings of increased Cp expression in cancers like hepatocarcinoma, where the intracellular copper level is higher in a redox compromised environment.
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Perea-García, Ana, Amparo Andrés-Bordería, Peter Huijser, and Lola Peñarrubia. "The Copper-microRNA Pathway Is Integrated with Developmental and Environmental Stress Responses in Arabidopsis thaliana." International Journal of Molecular Sciences 22, no. 17 (September 2, 2021): 9547. http://dx.doi.org/10.3390/ijms22179547.
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As an essential nutrient, copper (Cu) scarcity causes a decrease in agricultural production. Cu deficiency responses include the induction of several microRNAs, known as Cu-miRNAs, which are responsible for degrading mRNAs from abundant and dispensable cuproproteins to economize copper when scarce. Cu-miRNAs, such as miR398 and miR408 are conserved, as well as the signal transduction pathway to induce them under Cu deficiency. The Arabidopsis thaliana SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) family member SPL7 binds to the cis-regulatory motifs present in the promoter regions of genes expressed under Cu deficiency, including Cu-miRNAs. The expression of several other SPL transcription factor family members is regulated by miR156. This regulatory miR156-SPL module plays a crucial role in developmental phase transitions while integrating internal and external cues. Here, we show that Cu deficiency also affects miR156 expression and that SPL3 overexpressing plants, resistant to miR156 regulation, show a severe decrease in SPL7-mediated Cu deficiency responses. These include the expression of Cu-miRNAs and their targets and is probably due to competition between SPL7 and miR156-regulated SPL3 in binding to cis-regulatory elements in Cu-miRNA promoters. Thus, the conserved SPL7-mediated Cu-miRNA pathway could generally be affected by the miR156-SPL module, thereby underscoring the integration of the Cu-miRNA pathway with developmental and environmental stress responses in Arabidopsis thaliana.
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Villafane, Aramis, Yekaterina Voskoboynik, Ilona Ruhl, David Sannino, Yukari Maezato, Paul Blum, and Elisabetta Bini. "CopR of Sulfolobus solfataricus represents a novel class of archaeal-specific copper-responsive activators of transcription." Microbiology 157, no. 10 (October 1, 2011): 2808–17. http://dx.doi.org/10.1099/mic.0.051862-0.
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In trace amounts, copper is essential for the function of key enzymes in prokaryotes and eukaryotes. Organisms have developed sophisticated mechanisms to control the cytosolic level of the metal, manage its toxicity and survive in copper-rich environments. Here we show that the Sulfolobus CopR represents a novel class of copper-responsive regulators, unique to the archaeal domain. Furthermore, by disruption of the ORF Sso2652 (copR) of the Sulfolobus solfataricus genome, we demonstrate that the gene encodes a transcriptional activator of the copper-transporting ATPase CopA gene and co-transcribed copT, encoding a putative copper-binding protein. Disruption resulted in a loss of copper tolerance in two copR-knockout mutants, while metals such as zinc, cadmium and chromium did not affect their growth. Copper sensitivity in the mutant was linked to insufficient levels of expression of CopA and CopT. The findings were further supported by time-course inductively coupled plasma optical emission spectrometry measurements, whereby continued accumulation of copper in the S. solfataricus mutant was observed. In contrast, copper accumulation in the wild-type stabilized after reaching approximately 6 pg (µg total protein)–1. Complementation of the disrupted mutant with a wild-type copy of the copR gene restored the wild-type phenotype with respect to the physiological and transcriptional response to copper. These observations, taken together, lead us to propose that CopR is an activator of copT and copA transcription, and the member of a novel class of copper-responsive regulators.
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Bodenmiller, Diane M., and Stephen Spiro. "The yjeB (nsrR) Gene of Escherichia coli Encodes a Nitric Oxide-Sensitive Transcriptional Regulator." Journal of Bacteriology 188, no. 3 (February 1, 2006): 874–81. http://dx.doi.org/10.1128/jb.188.3.874-881.2006.
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ABSTRACT Microarray studies of the Escherichia coli response to nitric oxide and nitrosative stress have suggested that additional transcriptional regulators of this response remain to be characterized. We identify here the product of the yjeB gene as a negative regulator of the transcription of the ytfE, hmpA and ygbA genes, all of which are known to be upregulated by nitrosative stress. Transcriptional fusions to the promoters of these genes were expressed constitutively in a yjeB mutant, indicating that all three are targets for repression by YjeB. An inverted repeat sequence that overlaps the −10 element of all three promoters is proposed to be a binding site for the YjeB protein. A similar inverted repeat sequence was identified in the tehA promoter, which is also known to be sensitive to nitrosative stress. The ytfE, hmpA, ygbA, and tehA promoters all caused derepression of a ytfE-lacZ transcriptional fusion when present in the cell in multiple copies, presumably by a repressor titration effect, suggesting the presence of functional YjeB binding sites in these promoters. However, YjeB regulation of tehA was weak, as judged by the activity of a tehA-lacZ fusion, perhaps because YjeB repression of tehA is masked by other regulatory mechanisms. Promoters regulated by YjeB could be derepressed by iron limitation, which is consistent with an iron requirement for YjeB activity. The YjeB protein is a member of the Rrf2 family of transcriptional repressors and shares three conserved cysteine residues with its closest relatives. We propose a regulatory model in which the YjeB repressor is directly sensitive to nitrosative stress. On the basis of similarity to the nitrite-responsive repressor NsrR from Nitrosomonas europaea, we propose that the yjeB gene of E. coli be renamed nsrR.
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Danielli, Alberto, Simona Romagnoli, Davide Roncarati, Lorenzo Costantino, Isabel Delany, and Vincenzo Scarlato. "Growth Phase and Metal-Dependent Transcriptional Regulation of the fecA Genes in Helicobacter pylori." Journal of Bacteriology 191, no. 11 (April 3, 2009): 3717–25. http://dx.doi.org/10.1128/jb.01741-08.
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ABSTRACT Balancing metal uptake is essential for maintaining a proper intracellular metal concentration. Here, we report the transcriptional control exerted by the two metal-responsive regulators of Helicobacter pylori, Fur (iron-dependent ferric uptake regulator) and NikR (nickel-responsive regulator), on the three copies of the fecA genes present in this species. By monitoring the patterns of transcription throughout growth and in response to nickel, iron, and a metal chelator, we found that the expression of the three fecA genes is temporally regulated, responds to metals in different ways, and is selectively controlled by either one of the two regulators. fecA1 is expressed at a constant level throughout growth, and its expression is iron sensitive; the expression of fecA2 is mainly off, with minor expression coming up in late exponential phase. In contrast, the expression of fecA3 is maximal in early exponential phase, gradually decreases with time, and is repressed by nickel. The direct roles of Fur and NikR were studied both in vitro, by mapping the binding sites of each regulator on the promoter regions via DNase I footprinting analysis, and in vivo, by using primer extension analyses of the fecA transcripts in fur and nikR deletion strains. Overall, the results show that the expression of each fecA gene is finely tuned in response to metal availability, as well as during the bacterial growth phase, suggesting specific and dedicated functions for the three distinct FecA homologues.
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van Bakel, Harm, Eric Strengman, Cisca Wijmenga, and Frank C. P. Holstege. "Gene expression profiling and phenotype analyses of S. cerevisiae in response to changing copper reveals six genes with new roles in copper and iron metabolism." Physiological Genomics 22, no. 3 (August 11, 2005): 356–67. http://dx.doi.org/10.1152/physiolgenomics.00055.2005.
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Exhaustive microarray time course analyses of Saccharomyces cerevisiae during copper starvation and copper excess reveal new aspects of metal-induced gene regulation. Aside from identifying targets of established copper- and iron-responsive transcription factors, we find that genes encoding mitochondrial proteins are downregulated and that copper-independent iron transport genes are preferentially upregulated, both during prolonged copper deprivation. The experiments also suggest the presence of a small regulatory iron pool that links copper and iron responses. One hundred twenty-eight genes with putative roles in metal metabolism were further investigated by several systematic phenotype screens. Of the novel phenotypes uncovered, hsp12-Δ and arn1-Δ display increased sensitivity to copper, cyc1-Δ and crr1-Δ show resistance to high copper, vma13-Δ exhibits increased sensitivity to iron deprivation, and pep12-Δ results in reduced growth in high copper and low iron. Besides revealing new components of eukaryotic metal trafficking pathways, the results underscore the previously determined intimate links between iron and copper metabolism and mitochondrial and vacuolar function in metal trafficking. The analyses further suggest that copper starvation can specifically lead to downregulation of respiratory function to preserve iron and copper for other cellular processes.
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Ward, Sarah K., Elizabeth A. Hoye, and Adel M. Talaat. "The Global Responses of Mycobacterium tuberculosis to Physiological Levels of Copper." Journal of Bacteriology 190, no. 8 (February 8, 2008): 2939–46. http://dx.doi.org/10.1128/jb.01847-07.
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ABSTRACT Copper (Cu) is a required micronutrient, but it is highly toxic at high concentrations. Therefore, the levels of Cu must be tightly regulated in all living cells. The phagosome of Mycobacterium tuberculosis has been shown to have variable levels of Cu. Previously, we showed that M. tuberculosis contains a copper-sensitive operon, cso, that is induced during early infection in mice. In this study, we showed that ctpV, a gene in the cso operon, is a copper-responsive gene and most likely encodes an efflux pump for Cu. Furthermore, the transcription of key genes in the cso operon is induced by Cu ions and not by other ions, such as Ni and Zn ions. To elucidate copper-responsive genes other than those in the cso operon, we utilized DNA microarrays to profile mycobacterial responses to physiological levels of Cu. A transcriptome analysis identified a novel set of 30 copper-responsive genes in M. tuberculosis, one-half of which were induced only when toxic levels of Cu were added. Interestingly, several transcriptional regulators, including the furA gene, were induced during toxic Cu exposure, indicating that there was a generalized response to oxidative stressors rather than a Cu-specific response. In general, the Cu-induced transcriptome generated should help elucidate the role of the Cu response in maintaining M. tuberculosis survival during infection and could provide novel targets for controlling this virulent pathogen.
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Beaudoin, Jude, Seda Ekici, Fevzi Daldal, Samia Ait-Mohand, Brigitte Guérin, and Simon Labbé. "Copper transport and regulation in Schizosaccharomyces pombe." Biochemical Society Transactions 41, no. 6 (November 20, 2013): 1679–86. http://dx.doi.org/10.1042/bst2013089.
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The fission yeast Schizosaccharomyces pombe has been successfully used as a model to gain fundamental knowledge in understanding how eukaryotic cells acquire copper during vegetative growth. These studies have revealed the existence of a heteromeric Ctr4–Ctr5 plasma membrane complex that mediates uptake of copper within the cells. Furthermore, additional studies have led to the identification of one of the first vacuolar copper transporters, Ctr6, as well as the copper-responsive Cuf1 transcription factor. Recent investigations have extended the use of S. pombe to elucidate new roles for copper metabolism in meiotic differentiation. For example, these studies have led to the discovery of Mfc1, which turned out to be the first example of a meiosis-specific copper transporter. Whereas copper-dependent transcriptional regulation of the Ctr family members is under the control of Cuf1 during mitosis or meiosis, meiosis-specific copper transporter Mfc1 is regulated by the recently discovered transactivator Mca1. It is foreseeable that identification of novel meiotic copper-related proteins will serve as stepping stones to unravel fundamental aspects of copper homoeostasis.
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Mattie, Michael D., and Jonathan H. Freedman. "Copper-inducible transcription: regulation by metal- and oxidative stressresponsive pathways." American Journal of Physiology-Cell Physiology 286, no. 2 (February 2004): C293—C301. http://dx.doi.org/10.1152/ajpcell.00293.2003.
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Although copper is an essential metal, it is capable of catalyzing the formation of reactive oxygen species that can cause intracellular oxidative damage. We investigated the hypothesis that metal- and oxidative stress-responsive signal transduction pathways mediate the cellular and molecular responses associated with copper exposure. Transient transfection assays using COS-7 cells and mouse metallothionein-I (MT-I) or rat NAD(P)H:oxidoreductase 1-based reporter genes demonstrate that copper activates transcription via metal and antioxidant response elements. Concomitant with copper exposures is a decrease in the level of total glutathione and an increase in oxidized glutathione. Depletion of glutathione, before copper exposure, increases metal- and oxidative stress-inducible transcription and cytotoxicity. Pretreatment with the reactive oxygen scavengers aspirin or vitamin E provides partial protection against copper toxicity and reduces inducible transcription. Experiments using signal transduction inhibitors and a metal transcription factor (MTF)-1 null cell line demonstrate that copper-inducible MT-I transcription is regulated by protein kinase C and mitogen-activated protein kinase signaling pathways and requires MTF-1. The results of these studies indicate that copper activates transcription through both metal- and oxidative stress-responsive signal transduction pathways.
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Veldhuis, Nicholas A., Valentina A. Valova, Ann P. Gaeth, Nickless Palstra, Katherine M. Hannan, Belinda J. Michell, Leonard E. Kelly, et al. "Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATPase." International Journal of Biochemistry & Cell Biology 41, no. 12 (December 2009): 2403–12. http://dx.doi.org/10.1016/j.biocel.2009.06.008.
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Kim, Jeong-Ho, Jeffrey Polish, and Mark Johnston. "Specificity and Regulation of DNA Binding by the Yeast Glucose Transporter Gene Repressor Rgt1." Molecular and Cellular Biology 23, no. 15 (August 1, 2003): 5208–16. http://dx.doi.org/10.1128/mcb.23.15.5208-5216.2003.
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ABSTRACT Rgt1 is a glucose-responsive transcription factor that binds to the promoters of several HXT genes encoding glucose transporters in Saccharomyces cerevisiae and regulates their expression in response to glucose. Rgt1 contains a Zn2Cys6 binuclear cluster responsible for DNA binding. Most proteins that contain this sequence motif bind as dimers to regularly spaced pairs of the sequence CGG. However, there are no CGG pairs with regular spacing in promoters of genes regulated by Rgt1, suggesting that Rgt1 binds as a monomer to CGG or to another sequence. We identified the Rgt1 consensus binding site sequence 5′-CGGANNA-3′, multiple copies of which are present in all HXT promoters regulated by Rgt1. Rgt1 binds in vivo to multiple sites in the HXT3 promoter in a nonadditive, synergistic manner, leading to synergistic repression of HXT3 transcription. We show that glucose inhibits the DNA-binding ability of Rgt1, thereby relieving repression of HXT gene expression. This regulation of Rgt1 DNA-binding activity is caused by its glucose-induced phosphorylation: the hyperphosphorylated Rgt1 present in cells growing on high levels of glucose does not bind DNA in vivo or in vitro; dephosphorylation of this form of Rgt1 in vitro restores its DNA-binding ability. Furthermore, an altered Rgt1 that functions as a constitutive repressor remains hypophosphorylated when glucose is added to cells and binds DNA under these conditions. These results suggest that glucose regulates the DNA-binding ability of Rgt1 by inducing its phosphorylation.
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Das, Santanu, Saptarshi Maji, Ruturaj, Indira Bhattacharya, Tanusree Saha, Nabanita Naskar, and Arnab Gupta. "Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner." Journal of Cell Science 133, no. 24 (December 2, 2020): jcs246819. http://dx.doi.org/10.1242/jcs.246819.
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ABSTRACTThe Wilson disease protein, ATP7B maintains copper (herein referring to the Cu+ ion) homeostasis in the liver. ATP7B traffics from trans-Golgi network to endolysosomes to export excess copper. Regulation of ATP7B trafficking to and from endolysosomes is not well understood. We investigated the fate of ATP7B after copper export. At high copper levels, ATP7B traffics primarily to acidic, active hydrolase (cathepsin-B)-positive endolysosomes and, upon subsequent copper chelation, returns to the trans-Golgi network (TGN). At high copper, ATP7B colocalizes with endolysosomal markers and with a core member of retromer complex, VPS35. Knocking down VPS35 did not abrogate the copper export function of ATP7B or its copper-responsive anterograde trafficking to vesicles; rather upon subsequent copper chelation, ATP7B failed to relocalize to the TGN, which was rescued by overexpressing wild-type VPS35. Overexpressing mutants of the retromer complex-associated proteins Rab7A and COMMD1 yielded a similar non-recycling phenotype of ATP7B. At high copper, VPS35 and ATP7B are juxtaposed on the same endolysosome and form a large complex that is stabilized by in vivo photoamino acid labeling and UV-crosslinking. We demonstrate that retromer regulates endolysosome to TGN trafficking of copper transporter ATP7B in a manner that is dependent upon intracellular copper.
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Lamb, Teresa M., Justin Vickery, and Deborah Bell-Pedersen. "Regulation of Gene Expression inNeurospora crassawith a Copper Responsive Promoter." G3: Genes|Genomes|Genetics 3, no. 12 (October 18, 2013): 2273–80. http://dx.doi.org/10.1534/g3.113.008821.
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Grass, Gregor, and Christopher Rensing. "Genes Involved in Copper Homeostasis inEscherichia coli." Journal of Bacteriology 183, no. 6 (March 15, 2001): 2145–47. http://dx.doi.org/10.1128/jb.183.6.2145-2147.2001.
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ABSTRACT Recently, genes for two copper-responsive regulatory systems were identified in the Escherichia coli chromosome. In this report, data are presented that support a hypothesis that the putative multicopper oxidase CueO and the transenvelope transporter CusCFBA are involved in copper tolerance in E. coli.
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Baker, Jonathan, Sutthirat Sitthisak, Mrittika Sengupta, Miranda Johnson, R. K. Jayaswal, and Julie A. Morrissey. "Copper Stress Induces a Global Stress Response in Staphylococcus aureus and Represses sae and agr Expression and Biofilm Formation." Applied and Environmental Microbiology 76, no. 1 (October 30, 2009): 150–60. http://dx.doi.org/10.1128/aem.02268-09.
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ABSTRACT Copper is an important cofactor for many enzymes; however, high levels of copper are toxic. Therefore, bacteria must ensure there is sufficient copper for use as a cofactor but, more importantly, must limit free intracellular levels to prevent toxicity. In this study, we have used DNA microarray to identify Staphylococcus aureus copper-responsive genes. Transcriptional profiling of S. aureus SH1000 grown in excess copper identified a number of genes which fall into four groups, suggesting that S. aureus has four main mechanisms for adapting to high levels of environmental copper, as follows: (i) induction of direct copper homeostasis mechanisms; (ii) increased oxidative stress resistance; (iii) expression of the misfolded protein response; and (iv) repression of a number of transporters and global regulators such as Agr and Sae. Our experimental data confirm that resistance to oxidative stress and particularly to H2O2 scavenging is an important S. aureus copper resistance mechanism. Our previous studies have demonstrated that Eap and Emp proteins, which are positively regulated by Agr and Sae, are required for biofilm formation under low-iron growth conditions. Our transcriptional analysis has confirmed that sae, agr, and eap are repressed under high-copper conditions and that biofilm formation is indeed repressed under high-copper conditions. Therefore, our results may provide an explanation for how copper films can prevent biofilm formation on catheters.
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Stentz, Régis, Christophe Loizel, Christine Malleret, and Monique Zagorec. "Development of Genetic Tools forLactobacillus sakei: Disruption of the β-Galactosidase Gene and Use of lacZ as a Reporter Gene To Study Regulation of the Putative Copper ATPase, AtkB." Applied and Environmental Microbiology 66, no. 10 (October 1, 2000): 4272–78. http://dx.doi.org/10.1128/aem.66.10.4272-4278.2000.
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ABSTRACT Downstream from the ptsHI operon of Lactobacillus sakei, the genes atkY and atkB, organized in an operon, were observed. The two putative proteins, AtkB and AtkY, show sequence similarity to the Enterococcus hirae copper P-type ATPase, responsible for copper efflux, and its negative regulator. Characterization of AtkB as a copper P-type ATPase could not be demonstrated since an atkB mutant did not show any phenotype. Thus, another strategy was followed in order to investigate the transcriptional regulation of the atkYB locus, leading to the development of new genetic tools for L. sakei. A plasmid was constructed, the use of which allowed gene replacement at the lacLM locus in L. sakei by two successive crossovers. A strain deleted of the lacLM operon encoding the β-galactosidase of L. sakei was constructed by this method, and the Escherichia coli lacZ gene could then be used as a reporter gene to investigate the regulation ofatkYB. Results show that the atkYB operon is induced by small concentrations of CuSO4 (30 to 40 μM) but not when CuSO4 is omitted or added at higher concentrations.
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Kim, S. J., U. S. Onwuta, Y. I. Lee, R. Li, M. R. Botchan, and P. D. Robbins. "The retinoblastoma gene product regulates Sp1-mediated transcription." Molecular and Cellular Biology 12, no. 6 (June 1992): 2455–63. http://dx.doi.org/10.1128/mcb.12.6.2455-2463.1992.
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We have demonstrated that the retinoblastoma gene product (Rb) can positively regulate transcription from the fourth promoter of the insulinlike growth factor II gene. Two copies of a motif (the retinoblastoma control element) similar to that found in the human c-fos, transforming growth factor beta 1, and c-myc promoters are responsible for conferring Rb regulation to the fourth promoter of the insulinlike growth factor II gene. We have shown that the transcription factor Sp1 can bind to and stimulate transcription from the retinoblastoma control element motif. Moreover, by using a GAL4-Sp1 fusion protein, we have directly demonstrated that Rb positively regulates Sp1 transcriptional activity in vivo. These results indicate that Rb can function as a positive regulator of transcription and that Sp1 is one potential target, either directly or indirectly, for transcriptional regulation by Rb.
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Kim, S. J., U. S. Onwuta, Y. I. Lee, R. Li, M. R. Botchan, and P. D. Robbins. "The retinoblastoma gene product regulates Sp1-mediated transcription." Molecular and Cellular Biology 12, no. 6 (June 1992): 2455–63. http://dx.doi.org/10.1128/mcb.12.6.2455.
Full textAbstract:
We have demonstrated that the retinoblastoma gene product (Rb) can positively regulate transcription from the fourth promoter of the insulinlike growth factor II gene. Two copies of a motif (the retinoblastoma control element) similar to that found in the human c-fos, transforming growth factor beta 1, and c-myc promoters are responsible for conferring Rb regulation to the fourth promoter of the insulinlike growth factor II gene. We have shown that the transcription factor Sp1 can bind to and stimulate transcription from the retinoblastoma control element motif. Moreover, by using a GAL4-Sp1 fusion protein, we have directly demonstrated that Rb positively regulates Sp1 transcriptional activity in vivo. These results indicate that Rb can function as a positive regulator of transcription and that Sp1 is one potential target, either directly or indirectly, for transcriptional regulation by Rb.
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Bai, Lan, Xiao-hui Wang, Fei Song, Xiu-li Wang, and Yu-zhong Wang. "“AND” logic gate regulated pH and reduction dual-responsive prodrug nanoparticles for efficient intracellular anticancer drug delivery." Chemical Communications 51, no. 1 (2015): 93–96. http://dx.doi.org/10.1039/c4cc07012g.
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Chen, Jian, Yubing Si, Yibiao Liu, Saisai Wang, Shijie Wang, Ying Zhang, Baocheng Yang, Zuling Zhang, and Shouren Zhang. "Starch-regulated copper–terephthalic acid as a pH/hydrogen peroxide simultaneous-responsive fluorescent probe for lysosome imaging." Dalton Transactions 48, no. 34 (2019): 13017–25. http://dx.doi.org/10.1039/c9dt02193k.
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Yariuchi, Yusaku, Takashi Okamoto, Yoshiteru Noutoshi, and Taku Takahashi. "Responses of Polyamine-Metabolic Genes to Polyamines and Plant Stress Hormones in Arabidopsis Seedlings." Cells 10, no. 12 (November 24, 2021): 3283. http://dx.doi.org/10.3390/cells10123283.
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In plants, many of the enzymes in polyamine metabolism are encoded by multiple genes, whose expressions are differentially regulated under different physiological conditions. For comprehensive understanding of their regulation during the seedling growth stage, we examined the expression of polyamine metabolic genes in response to polyamines and stress-related plant hormones in Arabidopsis thaliana. While confirming previous findings such as induction of many of the genes by abscisic acid, induction of arginase genes and a copper amine oxidase gene, CuAOα3, by methyl jasmonate, that of an arginine decarboxylase gene, ADC2, and a spermine synthase gene, SPMS, by salicylic acid, and negative feedback regulation of thermospermine biosynthetic genes by thermospermine, our results showed that expressions of most of the genes are not responsive to exogenous polyamines. We thus examined expression of OsPAO6, which encodes an apoplastic polyamine oxidase and is strongly induced by polyamines in rice, by using the promoter-GUS fusion in transgenic Arabidopsis seedlings. The GUS activity was increased by treatment with methyl jasmonate but neither by polyamines nor by other plant hormones, suggesting a difference in the response to polyamines between Arabidopsis and rice. Our results provide a framework to study regulatory modules directing expression of each polyamine metabolic gene.
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Searle, P. F., G. W. Stuart, and R. D. Palmiter. "Building a metal-responsive promoter with synthetic regulatory elements." Molecular and Cellular Biology 5, no. 6 (June 1985): 1480–89. http://dx.doi.org/10.1128/mcb.5.6.1480-1489.1985.
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A fusion gene consisting of the promoter region from the mouse metallothionein-I gene joined to the coding region of the herpes simplex virus thymidine kinase gene is efficiently regulated by zinc in a transient assay when transfected into baby hamster kidney cells. Analysis of similar plasmids in which the metallothionein-I promoter region was mutated indicated the presence of multiple metal regulatory elements (MREs) between -176 and -44 base pairs from the cap site. To further investigate the function of MREs, we inserted a synthetic DNA fragment containing the sequence of MRE-a (the element between -55 and -44 base pairs) into the nonresponsive promoter of the thymidine kinase gene in various positions and configurations. Little or no induction by zinc was observed with single insertions of the regulatory sequence, whereas many different constructions having two copies of MRE-a were inducible. The precise position of the two MREs relative to each other or to the thymidine kinase promoter elements had a relatively small effect on the efficiency of induction, but the inducibility could be further increased by the introduction of more MRE-a sequences. MRE-a can function synergistically with the thymidine kinase distal promoter elements, but in the presence of the TATA box alone it functions as a positive, zinc-dependent promoter element.
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Searle, P. F., G. W. Stuart, and R. D. Palmiter. "Building a metal-responsive promoter with synthetic regulatory elements." Molecular and Cellular Biology 5, no. 6 (June 1985): 1480–89. http://dx.doi.org/10.1128/mcb.5.6.1480.
Full textAbstract:
A fusion gene consisting of the promoter region from the mouse metallothionein-I gene joined to the coding region of the herpes simplex virus thymidine kinase gene is efficiently regulated by zinc in a transient assay when transfected into baby hamster kidney cells. Analysis of similar plasmids in which the metallothionein-I promoter region was mutated indicated the presence of multiple metal regulatory elements (MREs) between -176 and -44 base pairs from the cap site. To further investigate the function of MREs, we inserted a synthetic DNA fragment containing the sequence of MRE-a (the element between -55 and -44 base pairs) into the nonresponsive promoter of the thymidine kinase gene in various positions and configurations. Little or no induction by zinc was observed with single insertions of the regulatory sequence, whereas many different constructions having two copies of MRE-a were inducible. The precise position of the two MREs relative to each other or to the thymidine kinase promoter elements had a relatively small effect on the efficiency of induction, but the inducibility could be further increased by the introduction of more MRE-a sequences. MRE-a can function synergistically with the thymidine kinase distal promoter elements, but in the presence of the TATA box alone it functions as a positive, zinc-dependent promoter element.
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Maertens, Laurens, Pauline Cherry, Françoise Tilquin, Rob Van Houdt, and Jean-Yves Matroule. "Environmental Conditions Modulate the Transcriptomic Response of Both Caulobacter crescentus Morphotypes to Cu Stress." Microorganisms 9, no. 6 (May 21, 2021): 1116. http://dx.doi.org/10.3390/microorganisms9061116.
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Bacteria encounter elevated copper (Cu) concentrations in multiple environments, varying from mining wastes to antimicrobial applications of copper. As the role of the environment in the bacterial response to Cu ion exposure remains elusive, we used a tagRNA-seq approach to elucidate the disparate responses of two morphotypes of Caulobacter crescentus NA1000 to moderate Cu stress in a complex rich (PYE) medium and a defined poor (M2G) medium. The transcriptome was more responsive in M2G, where we observed an extensive oxidative stress response and reconfiguration of the proteome, as well as the induction of metal resistance clusters. In PYE, little evidence was found for an oxidative stress response, but several transport systems were differentially expressed, and an increased need for histidine was apparent. These results show that the Cu stress response is strongly dependent on the cellular environment. In addition, induction of the extracytoplasmic function sigma factor SigF and its regulon was shared by the Cu stress responses in both media, and its central role was confirmed by the phenotypic screening of a sigF::Tn5 mutant. In both media, stalked cells were more responsive to Cu stress than swarmer cells, and a stronger basal expression of several cell protection systems was noted, indicating that the swarmer cell is inherently more Cu resistant. Our approach also allowed for detecting several new transcription start sites, putatively indicating small regulatory RNAs, and additional levels of Cu-responsive regulation.
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Willyerd, Karyn L., Amanda M. Kemp, and Angus L. Dawe. "Controlled Gene Expression in the Plant Pathogen Cryphonectria parasitica by Use of a Copper-Responsive Element." Applied and Environmental Microbiology 75, no. 16 (June 19, 2009): 5417–20. http://dx.doi.org/10.1128/aem.00899-09.
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ABSTRACT We have developed a tool for controlled expression of heterologous or ectopic genes in the chestnut pathogen Cryphonectria parasitica using the promoter region from a putative copper-regulated transporter gene. In addition, we have found that expression control via this system is not affected by the virulence-attenuating hypovirus CHV1-EP713.