Combined zebrafish-yeast chemical-genetic screens reveal gene–copper-nutrition interactions that modulate melanocyte pigmentation

Ishizaki, Hironori; Spitzer, Michaela; Wildenhain, Jan; Anastasaki, Corina; Zeng, Zhiqiang; Dolma, Sonam; Shaw, Michael; Madsen, Erik; Gitlin, Jonathan D.; Marais, Richard; Tyers, Mike; Patton, E. Elizabeth

doi:10.1242/dmm.005769

Cited by 39 publications

(40 citation statements)

References 62 publications

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“…As the MAPK pathway plays important roles in both cell proliferation and angiogenesis (15,30), Mek protein kinases may be critical targets for Cu chelators as chemotherapeutic agents. In support of this possibility, the Mek kinase inhibitor U0126 was recently identified in a screening for compounds that affect Cu metabolism in zebrafish (23).…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Turski

Brady

Kim

et al. 2012

Molecular and Cellular Biology

251

218

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c Copper (Cu) is essential for development and proliferation, yet the cellular requirements for Cu in these processes are not well defined. We report that Cu plays an unanticipated role in the mitogen-activated protein (MAP) kinase pathway. Ablation of the Ctr1 high-affinity Cu transporter in flies and mouse cells, mutation of Ctr1, and Cu chelators all reduce the ability of the MAP kinase kinase Mek1 to phosphorylate the MAP kinase Erk. Moreover, mice bearing a cardiac-tissue-specific knockout of Ctr1 are deficient in Erk phosphorylation in cardiac tissue. In vitro investigations reveal that recombinant Mek1 binds two Cu atoms with high affinity and that Cu enhances Mek1 phosphorylation of Erk in a dose-dependent fashion. Coimmunoprecipitation experiments suggest that Cu is important for promoting the Mek1-Erk physical interaction that precedes the phosphorylation of Erk by Mek1. These results demonstrate a role for Ctr1 and Cu in activating a pathway well known to play a key role in normal physiology and in cancer. Copper (Cu) is a metal ion that functions as a redox-active cofactor for a broad range of biochemical reactions, including mitochondrial oxidative phosphorylation, protection from reactive oxygen species, connective tissue maturation, iron absorption, neuropeptide biogenesis, and other processes (28, 43). Numerous studies point to the essentiality of Cu for normal growth and development, while aberrant Cu accumulation in tissues, as manifested in Wilson's disease patients, results in significant pathologies (33,35,42,47,60,61). However, the precise roles Cu plays and the mechanistic processes by which Cu drives cellular proliferation and growth are not well understood.The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is an evolutionarily conserved pathway involved in the control of many fundamental biological processes, including cell proliferation, apoptosis, survival, differentiation, motility, and metabolism (26,30). Aberrant Ras/MAPK signaling has significant consequences; loss of function of several components of the Ras/MAPK signaling cascade results in lethality, whereas gain-offunction mutations in many of the Ras/MAPK signaling components underlie cancer (2,12,26,55).Here we identify the Ctr1 high-affinity Cu ϩ transporter, conserved from yeast to humans, as being important for stimulation of the MAPK Erk in response to extracellular growth factor-mediated activation of the Ras signaling pathway. Moreover, genetic, physiological, and biochemical experiments point to a direct role for Cu in the ability of the MAPK kinase Mek1 to phosphorylate Erk in fruit flies, cultured cells, and mice. These studies suggest that the MAPK signaling pathway is a key cellular proliferation pathway that is stimulated by Cu and may be a direct target of potent cancer chemotherapeutics that function via Cu chelation. MATERIALS AND METHODS Drosophila melanogaster stocks and crosses. Phantom Gal4, UAS mCD8::GFP/TM6, Tb flies were from Michael O'Connor, University of Minnesota (44). The UAS-Ctr1ARNA...

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Section: Discussionmentioning

confidence: 99%

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Turski

Brady

Kim

et al. 2012

Molecular and Cellular Biology

251

218

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“…Copper is a key trace mineral in mink nutrition in terms of its role in hemoglobin formation and normal pigmentation of fur (Ajayi 2005;Ishizaki et al 2010). The element is also an essential component of many enzyme systems such as cytochrome C oxidase, amino oxidase, polyphenol oxidase, ferroxidase, and copper-zinc superoxiode dismutase (Gaetke and Chow 2003).…”

Section: Introductionmentioning

confidence: 99%

Effects of dietary copper supplementation on nutrient digestibility, serum biochemical indices, and growth rate of young female mink (Neovison vison)

Wu¹,

Yang²,

Liu³

et al. 2014

CZECH J ANIM SCI

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ABSTRACT:The objective of this study was to determine whether nutrient digestibility and growth performance of mink were affected by different dietary copper levels. Ninety-six 60-day-old healthy female minks were randomly assigned to 8 treatment groups with 12 animals in each group and fed a diet supplemented with either 0, 4, 8, 16, 32, 64, 128 or 256 mg/kg copper as CuSO 4 × 5H 2 O, respectively. Our data showed that body weight and average daily gain increased (linear and quadratic, P < 0.05) as Cu increased in the diet, the highest body weight and average daily gain were seen in the Cu32 group. Feed : gain ratio responded in a linear (P = 0.0025) fashion with increasing level of Cu, the lowest feed : gain ratio was seen in the Cu64 group. Digestibility of ether extract responded in a linear (P = 0.0190) fashion with increasing level of Cu. There were no differences in apparent digestibility of dry matter, CP, and gross energy among groups (P > 0.05). N retention linearly (P = 0.0363) responded to increasing levels of Cu. Glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase increased (linear and quadratic, P < 0.05) as Cu increased in the diet; the highest glutamicoxalacetic transaminase and glutamic-pyruvic transaminase were seen in the Cu256 group. Total protein of the minks was similar among the treatments, however, albumin in serum responded in a linear (P = 0.0370) and quadratic (P = 0.0049) fashion with increasing level of Cu. The activity of ceruloplasmin responded in a linear (P = 0.0001) and quadratic (P = 0.0203) fashion with increasing level of Cu. The activity of Cu-Zn superoxide dismutase responded in a linear (P = 0.0010) fashion with increasing level of Cu. Our results indicate that supplemental Cu plays an important role in the growth performance of mink, helping young female mink digest and efficiently utilize added dietary fat.

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“…1). Several studies applying the zebrafish model in a similar manner have recently been reported in the literature (Ishizaki et al, 2010;Behra et al, 2004;Davidson et al, 2008;Molina et al, 2009;Arslanova et al, 2010;Buckley et al, 2010;Hao et al, 2010;Kokel et al, 2010;Rihel et al, 2010). In the sections below, we summarize some of these examples to illustrate the utility of the zebrafish embryo as a promising system for detecting off-target effects of drug candidates.…”

Section: Primermentioning

confidence: 94%

The zebrafish embryo as a model for assessing off-target drug effects

Strähle

Grabher

2010

Disease Models &Amp; Mechanisms

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Although first used experimentally for the genetic analysis of vertebrate development and neurobiology, the zebrafish has been adapted as a model for many human diseases. In recent years, the zebrafish embryo has increasingly attracted the attention of chemists and pharmacologists for its utility in identifying chemicals with pharmacological activity in a whole-animal context. Its experimental virtues make it an ideal system with which to identify new bioactive molecules, and to assess their toxicity and teratogenicity at medium-to-high throughput. More recently, the zebrafish embryo has been applied to identify off-target effects of drug candidates. Here, we discuss the value of the zebrafish embryo for detecting off-target effects, and propose that this model could be useful for improving the efficiency of the drug-development pipeline.

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Combined zebrafish-yeast chemical-genetic screens reveal gene–copper-nutrition interactions that modulate melanocyte pigmentation

Cited by 39 publications

References 62 publications

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Effects of dietary copper supplementation on nutrient digestibility, serum biochemical indices, and growth rate of young female mink (Neovison vison)

The zebrafish embryo as a model for assessing off-target drug effects

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