Yeast Lacking Cu-Zn Superoxide Dismutase Show Altered Iron Homeostasis

Freitas, Jeane M. De; Liba, Amir; Meneghini, Rogério; Valentine, Joan Selverstone; Gralla, Edith Butler

doi:10.1074/jbc.275.16.11645

Cited by 84 publications

(63 citation statements)

References 48 publications

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“…The increased Cu efflux seems to lead to a Cu deficiency and a subsequently reduced SOD-1 activity. The enzyme occurs in high intracellular concentrations (10 M in yeast) and has a role in Zn homeostasis and Fe metabolism (40)(41)(42). Two studies (43,44) have shown that a disturbed metal-ion homeostasis with elevated serum Cu levels occurs in AD and Down's patients, and lowered levels in postmortem AD brain (25).…”

Section: Discussionmentioning

confidence: 99%

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Bayer

Schäfer

Simons

et al. 2003

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

312

254

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The Cu-binding ␤-amyloid precursor protein (APP), and the amyloid A␤ peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in A␤ levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS A␤ before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

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Section: Discussionmentioning

confidence: 99%

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Bayer

Schäfer

Simons

et al. 2003

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

312

254

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“…There are previous reports that deletion of CuZn and/or manganese SOD genes leads to accumulation of free iron in S. cerevisiae cells (70,71). Thus it appears that Cap2-mediated repression of SOD gene expression could additionally mobilize iron in vivo.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

Singh¹,

Prasad²,

Sinha³

et al. 2011

Journal of Biological Chemistry

209

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Iron homeostasis is highly regulated in organisms across evolutionary time scale as iron is essential for various cellular processes. In a computational screen, we identified the Yap/bZIP domain family in Candida clade genomes. Cap2/Hap43 is essential for C. albicans growth under iron-deprivation conditions and for virulence in mouse. Cap2 has an amino-terminal bipartite domain comprising a fungal-specific Hap4-like domain and a bZIP domain. Our mutational analyses showed that both the bZIP and Hap4-like domains perform critical and independent functions for growth under iron-deprivation conditions. Transcriptome analysis conducted under iron-deprivation conditions identified about 16% of the C. albicans ORFs that were differentially regulated in a Cap2-dependent manner. Microarray data also suggested that Cap2 is required to mobilize iron through multiple mechanisms; chiefly by activation of genes in three iron uptake pathways and repression of iron utilizing and iron storage genes. The expression of HAP2, HAP32, and HAP5, core components of the HAP regulatory complex was induced in a Cap2-dependent manner indicating a feed-forward loop. In a feed-back loop, Cap2 repressed the expression of Sfu1, a negative regulator of iron uptake genes. Cap2 was coimmunoprecipitated with Hap5 from cell extracts prepared from iron-deprivation conditions indicating an in vivo association. ChIP assays demonstrated Hap32-dependent recruitment of Hap5 to the promoters of FRP1 (Cap2-induced) and ACO1 (Cap2-repressed). Together our data indicates that the Cap2-HAP complex functions both as a positive and a negative regulator to maintain iron homeostasis in C. albicans.

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“…The mechanism of iron utilization and homeostasis has been elucidated in Saccharomyces cerevisiae (Kwak and Kosman, 2006). Fe 3+ is first reduced to Fe 2+ by two plasma membrane proteins, Fre1 and Fre2, then transported by the low-afffinity iron transporter Fet4 (apparent Km of 30 mM) in iron-repleted conditions, or by the multicopper oxidase Fet3, a high afffinity iron system (apparent Km of 0.15 mM) in iron-depleted conditions (De Freitas et al, 2000;Dix et al, 1997). S. cerevisiae uses two iron-responsive transcription factors, Aft1/2, to activate the transcription of a cluster of genes in the iron regulon that is implicated in iron-sulfur biosynthesis, heme utilization, and iron intracellular redistribution (Courel et al, 2005;Rutherford et al, 2003, Shakoury-Elizeh et al, 2004.…”

Section: Introductionmentioning

confidence: 99%

Expression Profiling Reveals an Unexpected Growth-Stimulating Effect of Surplus Iron on the Yeast Saccharomyces cerevisiae

Wang

2012

Molecules and Cells

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Iron homeostasis plays a crucial role in growth and division of cells in all kingdoms of life. Although yeast iron metabolism has been extensively studied, little is known about the molecular mechanism of response to surplus iron. In this study, expression profiling of Saccharomyces cerevisiae in the presence of surplus iron revealed a dual effect at 1 and 4 h. A cluster of stress-responsive genes was upregulated via activation of the stress-resistance transcription factor Msn4, which indicated the stress effect of surplus iron on yeast metabolism. Genes involved in aerobic metabolism and several anabolic pathways are also upregulated in iron-surplus conditions, which could significantly accelerate yeast growth. This dual effect suggested that surplus iron might participate in a more complex metabolic network, in addition to serving as a stress inducer. These findings contribute to our understanding of the global response of yeast to the fluctuating availability of iron in the environment.

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Yeast Lacking Cu-Zn Superoxide Dismutase Show Altered Iron Homeostasis

Cited by 84 publications

References 48 publications

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Cap2-HAP Complex Is a Critical Transcriptional Regulator That Has Dual but Contrasting Roles in Regulation of Iron Homeostasis in Candida albicans

Expression Profiling Reveals an Unexpected Growth-Stimulating Effect of Surplus Iron on the Yeast Saccharomyces cerevisiae

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