Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At the molecular level, little is known about the transport of copper across plant membranes. We have isolated an Arabidopsis thaliana cDNA by complementation of a mutant (ctr1-3) of Saccharomyces cerevisiae defective in high affinity copper uptake. This cDNA codes for a highly hydrophobic protein (COPT1) of 169 amino acid residues and with three putative transmembrane domains. Most noteworthy, the first 44 residues display significant homology to the methionine- and histidine-rich copper binding domain of three bacterial copper binding proteins, among these a copper transporting ATPase. Mutant yeast cells expressing COPT1 exhibit nearly wild type behavior with regard to growth on a nonfermentable carbon source and resistance to copper and iron starvation. Expression of COPT1 is also associated with an increased sensitivity to copper toxicity. Additionally, COPT1 shows significant homology to an open reading frame of 189 amino acid residues on yeast chromosome VIII. This gene (CTR2) may encode an additional yeast metal transporter able to mediate the uptake of copper. A mutation in CTR2 displays a higher level of resistance to toxic copper concentrations. Overexpression of CTR2 provides increased resistance to copper starvation and is also associated with an increased sensitivity to copper toxicity. The amino acid sequence of CTR2, like Arabidopsis COPT1, contains three potential transmembrane domains. Taken together, the data suggest that a plant metal transporter, which is most likely involved in the transport of copper, has been identified.
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PMID:Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue. 749 55

Down-regulation of copper transporter 1 (CTR1) reduces uptake and sensitivity, whereas down-regulation of CTR2 enhances both. Cisplatin (DDP) triggers the rapid degradation of CTR1 and thus limits its own accumulation. We sought to determine the effect of DDP and copper on the expression of CTR2. Changes in CTR1 and CTR2 mRNA and protein levels in human ovarian carcinoma 2008 cells and ATOX1(+/+) and ATOX1(-/-) mouse embryo fibroblasts in response to exposure to DDP and copper were measured by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and deconvolution microscopy. DDP triggered rapid degradation of CTR1 in 2008 human ovarian cancer cells. However, it increased the expression of CTR2 mRNA and protein levels. Expression of CTR2 was heavily modulated by changes in intracellular copper concentration; copper depletion produced rapid disappearance of CTR2, whereas excess copper increased the level of CTR2 protein. This increase was associated with an increase in CTR2 mRNA and prolongation of the CTR2 half-life. Consistent with prior observations that short hairpin RNA interference-mediated knockdown of CTR2 enhanced DDP uptake and tumor cell kill, reduction of CTR2 by copper starvation also enhanced DDP uptake and cytotoxicity. Comparison of the ability of copper and DDP to modulate the expression of CTR1 in ATOX1(+/+) and ATOX1(-/-) indicated that ATOX1 participates in the regulation of CTR2 expression. Unlike CTR1, the expression of CTR2 is increased rather than decreased by DDP. Therefore, these two copper transporters have opposite effects on DDP sensitivity. CTR2 expression is regulated by copper availability via the copper-dependent regulator ATOX1.
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PMID:Regulation of copper transporter 2 expression by copper and cisplatin in human ovarian carcinoma cells. 2019 31

Cryptococcus neoformans is a human opportunistic fungal pathogen responsible for approximately 1/3 of HIV/AIDS deaths worldwide. This budding yeast expresses a polysaccharide capsule necessary for virulence. Capsule production inhibits phagocytosis by macrophages. Here we describe results that link copper homeostasis to capsule production and the inhibition of phagocytosis. Specifically, using Agrobacterium-mediated insertional mutagenesis, we identified an insertion in the promoter region of the putative copper transporter-encoding gene CTR2 that results in reduced expression of CTR2 and increased phagocytosis by murine RAW264.7 macrophages. The mutant also displayed sensitivity to copper starvation and defects in polysaccharide capsule production and melanization. These defects were all reversed by genetic correction of the promoter insertion by homologous targeting. Several melanization-defective mutants identified previously, those in the RIM20, RIM101, and VPS25 genes, also display sensitivity to copper starvation, reduced capsule production and increased phagocytosis. Together these results indicate a previously undescribed link between copper homeostasis to polysaccharide capsule production and phagocytosis inhibition in Cryptococcus neoformans.
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PMID:Ctr2 links copper homeostasis to polysaccharide capsule formation and phagocytosis inhibition in the human fungal pathogen Cryptococcus neoformans. 2082 73

Copper is an indispensable metal for life. For convenience of genetic manipulation and sharing similar metabolic pathway of metals with mammalian cells, the yeast Saccharomyces cerevisiae is widely used for metal homeostasis studies. Storage and mobilization of copper ions in yeast vacuoles or mammalian lysosomes are important for cells to avoid their toxicity and elevate their utility. Though regulation of other genes involved in copper homeostasis is well understood, the regulation of gene encoding low-affinity copper transporter Ctr2p, which mediates mobilization of vacuolar or lysosomal stored copper ions, is still unclear. In this study, we found that copper depletion can upregulate yeast CTR2 gene transcription while copper overload downregulate it. The copper-depletion induced CTR2 transcription can be abrogated by genetic deletion of copper-sensing transcription factor Mac1p. Though absent of consensus Mac1p binding sequences, CTR2 promoter region is demonstrated to be occupied by Mac1p, according to our results of chromatin immunoprecipitation (ChIP) assay. Overexpression of Mac1p can upregulate CTR2 transcription and partially complement the growth defect of copper-deficient yeast strain. Taken together, our results suggest that Mac1p can activate the expression of vacuolar copper transporter Ctr2p in response to copper deficiency, resulting in yeast resistance to copper starvation.
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PMID:Low-affinity copper transporter CTR2 is regulated by copper-sensing transcription factor Mac1p in Saccharomyces cerevisiae. 2244 56