Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis.

Ooi, Chean Eng; Rabinovich, Efrat; Dancis, Andrew; Bonifacino, Juan S.; Klausner, Richard D.

doi:10.1002/j.1460-2075.1996.tb00720.x

Cited by 193 publications

(185 citation statements)

References 55 publications

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“…2A). However, we cannot rule out that the HA epitope tag alters putative COPT1 posttranslational regulatory mechanisms, including Cu-induced endocytosis, degradation, and transport blockage, which have been previously described for other eukaryotic high-affinity Cu transporters of the CTR family (Ooi et al, 1996;Petris et al, 2003;Guo et al, 2004;Liu et al, 2007). In this sense, although the Cys residues at the yeast Ctr1 C terminus are dispensable for Cu transport, they have been postulated to serve as Cu sensors and to play a crucial role in preventing Cu uptake when intracellular Cu levels rise (Wu et al, 2009).…”

Section: Discussionmentioning

confidence: 88%

Deregulated Copper Transport Affects Arabidopsis Development Especially in the Absence of Environmental Cycles

et al. 2010

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Copper is an essential cofactor for key processes in plants, but it exerts harmful effects when in excess. Previous work has shown that the Arabidopsis (Arabidopsis thaliana) COPT1 high-affinity copper transport protein participates in copper uptake through plant root tips. Here, we show that COPT1 protein localizes to the plasma membrane of Arabidopsis cells and the phenotypic effects of transgenic plants overexpressing either COPT1 or COPT3, the latter being another high-affinity copper transport protein family member. Both transgenic lines exhibit increased endogenous copper levels and are sensitive to the copper in the growth medium. Additional phenotypes include decreased hypocotyl growth in red light and differentially affected flowering times depending on the photoperiod. Furthermore, in the absence of environmental cycles, such as light and temperature, the survival of plants overexpressing COPT1 or COPT3 is compromised. Consistent with altered circadian rhythms, the expression of the nuclear circadian clock genes CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) is substantially reduced in either COPT1-or COPT3-overexpressing plants. Copper affects the amplitude and the phase, but not the period, of the CCA1 and LHY oscillations in wild-type plants. Copper also drives a reduction in the expression of circadian clock output genes. These results reveal that the spatiotemporal control of copper transport is a key aspect of metal homeostasis that is required for Arabidopsis fitness, especially in the absence of environmental cues.

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Section: Discussionmentioning

confidence: 88%

Deregulated Copper Transport Affects Arabidopsis Development Especially in the Absence of Environmental Cycles

et al. 2010

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“…Nevertheless, we still found it intriguing that hCTR1 and Arabidopsis COPT1, two proteins from two evolutionarily distant organisms, both function very well in yeast despite a complete lack of the region homologous to the carboxyl terminus of CTR1. This region has recently been shown to be involved in endocytosis of CTR1 in the presence of excess copper (33). The same authors showed that neither endocytosis nor the bulk of the region is necessary for copper transportation.…”

Section: Discussionmentioning

confidence: 98%

hCTR1: A human gene for copper uptake identified by complementation in yeast

Zhou

Gitschier

1997

Proc. Natl. Acad. Sci. U.S.A.

509

336

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The molecular mechanisms responsible for the cellular uptake of copper in mammalian cells are unknown. We describe isolation of a human gene involved in this process by complementation of the yeast high-affinity copper uptake mutant, ctr1. Besides complementing ctr1 growth defect on nonfermentable media, the human gene also rescues iron transport and SOD1 defects in ctr1 yeast. Overexpression of the gene in yeast leads to vulnerability to the toxicity of copper overload. In addition, its expression in ctr1 yeast significantly increases the level of cellular copper, as demonstrated by atomic absorption. We propose this gene as a candidate for high-affinity copper uptake in humans and by analogy have named it hCTR1. The hCTR1 and yeast CTR1 predicted transmembrane proteins are 29% identical, but the human protein is substantially smaller in both the extracellular metal-binding and intracellular domains. An additional human gene similar to hCTR1, here named hCTR2, was identified in a database search. Both hCTR1 and hCTR2 are expressed in all human tissues examined, and both genes are located in 9q31͞32. These studies, together with the previously recognized functional and sequence similarity between the Menkes͞Wilson copper export proteins and CCC2 in yeast, demonstrate that similar copper homeostatic mechanisms are used in these evolutionarily divergent organisms.

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“…Cell pellets were collected by a 30-s centrifugation at 8,000 ϫ g and quickly placed in liquid nitrogen. Cell extracts were then made by standard alkaline lysis and trichloroacetic acid (TCA) precipitation procedures with some modifications (26). Briefly, 2.7 ϫ 10 7 cells were resuspended in 500 l of cold double-distilled water (ddH 2 O).…”

Section: Methodsmentioning

confidence: 99%

Ubp8 and SAGA Regulate Snf1 AMP Kinase Activity

Wilson

Koutelou

Hirsch

et al. 2011

Molecular and Cellular Biology

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Posttranslational modifications of histone proteins play important roles in the modulation of gene expression. The Saccharomyces cerevisiae (yeast) 2-MDa SAGA (Spt-Ada-Gcn5) complex, a well-studied multisubunit histone modifier, regulates gene expression through Gcn5-mediated histone acetylation and Ubp8-mediated histone deubiquitination. Using a proteomics approach, we determined that the SAGA complex also deubiquitinates nonhistone proteins, including Snf1, an AMP-activated kinase. Ubp8-mediated deubiquitination of Snf1 affects the stability and phosphorylation state of Snf1, thereby affecting Snf1 kinase activity. Others have reported that Gal83 is phosphorylated by Snf1, and we found that deletion of UBP8 causes decreased phosphorylation of Gal83, which is consistent with the effects of Ubp8 loss on Snf1 kinase functions. Overall, our data indicate that SAGA modulates the posttranslational modifications of Snf1 in order to fine-tune gene expression levels.Ubiquitination of cellular targets regulates many biological processes, from intracellular trafficking to gene expression. Although ubiquitination by ubiquitin (Ub) ligases is widely studied, less is known about subsequent deubiquitination (DUB) of cellular substrates. The identification of genes coding 16 deubiquitinases in the Saccharomyces cerevisiae (yeast) genome and genes coding at least 60 deubiquitinases in the human genome suggests that not only is deubiquitination important but also that deubiquitination may also occur in a substratespecific manner to regulate specific cellular processes. Despite the lack of knowledge of the targets of many of these deubiquitinases, it is known that some of these enzymes impact cellular growth and function (3,21,46). Overexpression of certain deubiquitinases is associated with progression of malignancy in neuroblastomas and a variety of carcinomas, indicating that these enzymes may be oncogenic (27,31,38).USP22, a deubiquitinase associated with the SAGA histone acetyltransferase (HAT) complex, was identified as a member of an 11-gene "death-from-cancer" signature that serves as a predictor of treatment resistance, aggressive growth, and metastasis of human tumors when overexpressed (7,8). The SAGA complex is highly conserved, and its functions are best characterized in yeast (4,9,17,23,35). In addition to acetylating histone H3 via the Gcn5 subunit, SAGA also proteolytically cleaves ubiquitin moieties from histone H2B via the Ubp8 subunit, which is an ortholog of USP22 (13, 47). Ubp8-mediated deubiquitination of histone H2B regulates the expression of target genes by modulating the level of histone H3 lysine 4 methylation, a mark that is associated with active transcription (13). In addition, Ubp8 facilitates the recruitment of the Cterminal domain kinase (Ctk1) to target gene promoters via histone H2B deubiquitination, which facilitates the transition from transcription initiation to elongation (43).Interestingly, recent studies indicate that the functions of USP22 extend beyond histone H2B, as it also deubiquiti...

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Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis.

Cited by 193 publications

References 55 publications

Deregulated Copper Transport Affects Arabidopsis Development Especially in the Absence of Environmental Cycles

Deregulated Copper Transport Affects Arabidopsis Development Especially in the Absence of Environmental Cycles

hCTR1: A human gene for copper uptake identified by complementation in yeast

Ubp8 and SAGA Regulate Snf1 AMP Kinase Activity

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