The Keap1-Nrf2 system is the major regulatory pathway of cytoprotective gene expression against oxidative and/or electrophilic stresses. Keap1 acts as a stress sensor protein in this system. While Keap1 constitutively suppresses Nrf2 activity under unstressed conditions, oxidants or electrophiles provoke the repression of Keap1 activity, inducing the Nrf2 activation. However, the precise molecular mechanisms behind the liberation of Nrf2 from Keap1 repression in the presence of stress remain to be elucidated. We hypothesized that oxidative and electrophilic stresses induce the nuclear accumulation of Nrf2 by affecting the Keap1-mediated rapid turnover of Nrf2, since such accumulation was diminished by the protein synthesis inhibitor cycloheximide. While both the Cys273 and Cys288 residues of Keap1 are required for suppressing Nrf2 nuclear accumulation, treatment of cells with electrophiles or mutation of these cysteine residues to alanine did not affect the association of Keap1 with Nrf2 either in vivo or in vitro. Rather, these treatments impaired the Keap1-mediated proteasomal degradation of Nrf2. These results support the contention that Nrf2 protein synthesized de novo after exposure to stress accumulates in the nucleus by bypassing the Keap1 gate and that the sensory mechanism of oxidative and electrophilic stresses is closely linked to the degradation mechanism of Nrf2.

Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1.

Ever since the beginning of biochemical analysis, yeast has been a pioneering model for studying the regulation of eukaryotic metabolism. During the last three decades, the combination of powerful yeast genetics and genome-wide approaches has led to a more integrated view of metabolic regulation. Multiple layers of regulation, from suprapathway control to individual gene responses, have been discovered. Constitutive and dedicated systems that are critical in sensing of the intra- and extracellular environment have been identified, and there is a growing awareness of their involvement in the highly regulated intracellular compartmentalization of proteins and metabolites. This review focuses on recent developments in the field of amino acid, nucleotide, and phosphate metabolism and provides illustrative examples of how yeast cells combine a variety of mechanisms to achieve coordinated regulation of multiple metabolic pathways. Importantly, common schemes have emerged, which reveal mechanisms conserved among various pathways, such as those involved in metabolite sensing and transcriptional regulation by noncoding RNAs or by metabolic intermediates. Thanks to the remarkable sophistication offered by the yeast experimental system, a picture of the intimate connections between the metabolomic and the transcriptome is becoming clear.

https://www.genetics.org/content/genetics/190/3/885.full.pdf

Regulation of amino acid, nucleotide and phosphate metabolism in Saccharomyces cerevisiae

Control of eukaryotic cell proliferation involves an extended regulatory network, the complexity of which has made it difficult to understand the basic principles of the cell cycle. To investigate the core engine of the mitotic cycle we have generated a minimal control network in fission yeast that efficiently sustains cellular reproduction. Here we demonstrate that orderly progression through the major events of the cell cycle can be driven by oscillation of an engineered monomolecular cyclin-dependent protein kinase (CDK) module lacking much of the canonical regulation. We show further that the CDK oscillator acts as the primary organizer of the cell cycle, imposing timing and directionality to a system of two CDK activity thresholds that define independent cell cycle phases. We propose that this simple core architecture forms the basic control of the eukaryotic cell cycle.

Driving the cell cycle with a minimal CDK control network

Plants can't move away and are therefore continuously confronted with unfavorable environmental conditions (such as soil salinity, drought, heat, cold, flooding and heavy metal contamination). Among heavy metals, cadmium (Cd) is a non-essential and toxic metal, rapidly taken up by roots and accumulated in various plant tissues which hamper the crop growth and productivity worldwide. Plants employ various strategies to counteract the inhibitory effect of Cd, among which nutrient management is one of a possible way to overcome Cd toxicity. Sulfur (S) uptake and assimilation are crucial for determining crop yield and resistance to Cd stress. Cd affects S assimilation pathway which leads to the activation of pathway responsible for the synthesis of cysteine (Cys), a precursor of glutathione (GSH) biosynthesis. GSH, a non-protein thiol acts as an important antioxidant in mitigating Cd-induced oxidative stress. It also plays an important role in phytochelatins (PCs) synthesis, which has a proven role in Cd detoxification. Therefore, S assimilation is considered a crucial step for plant survival under Cd stress. The aim of this review is to discuss the regulatory mechanism of S uptake and assimilation, GSH and PC synthesis for Cd stress tolerance in crop plants.

https://www.tandfonline.com/doi/pdf/10.4161/psb.6.2.14880

Cadmium stress tolerance in crop plants Probing the role of sulfur

Cadmium at high dose perturbs growth, photosynthesis and nitrogen metabolism while at low dose it up regulates sulfur assimilation and antioxidant machinery in garden cress (Lepidium sativum L.)

Activity of the Met4 transcription factor is antagonized by the SCFMet30 ubiquitin ligase by degradation-dependent and degradation-independent mechanisms, in minimal and rich nutrient conditions, respectively. In this study, we show that the heavy metal Cd2+ over-rides both mechanisms to enable rapid Met4-dependent induction of metabolic networks needed for production of the antioxidant and Cd2+-chelating agent glutathione. Cd2+ inhibits SCFMet30 activity through rapid dissociation of the F-box protein Met30 from the holocomplex. In minimal medium, dissociation of SCFMet30 complex is sufficient to impair the methionine-induced degradation of Met4. In rich medium, dissociation of the SCFMet30 complex is accompanied by a deubiquitylation mechanism that rapidly removes inhibitory ubiquitin moieties from Met4. Post-translational control of SCFMet30 assembly by a physiological stress to allow rapid induction of a protective gene expression program represents a novel mode of regulation in the ubiquitin system.

/pdf/inducible-dissociation-of-scfmet30-ubiquitin-ligase-mediates-2qo1xr679x.pdf

Inducible dissociation of SCFMet30 ubiquitin ligase mediates a rapid transcriptional response to cadmium

Cyclin-dependent kinase (CDK) Tyr15 phosphorylation plays a major role in regulating G2/M CDKs, but the role of this phosphorylation in regulating G1/S CDKs is less clear. We have studied the regulation and function of Cdc2-Tyr15 phosphorylation in the fission yeast Schizosaccharomyces pombe G1/S CDK Cig2/Cdc2. This complex is subject to high level Cdc2-Tyr15 phosphorylation inhibiting its kinase activity in hydroxyurea-treated cells blocked in S-phase. We show that this Tyr15 phosphorylation is required to maintain efficient mitotic checkpoint arrest, because Cig2 accumulates during the block and this accumulation can advance mitotic onset. This mitotic induction operates, at least in part, through activation of the normal G2/M CDK complex Cdc13/Cdc2. Thus, Tyr15 phosphorylation of G1/S CDK complexes is important in the checkpoint control blocking mitotic onset when DNA replication is inhibited.

/pdf/g1-s-cdk-is-inhibited-to-restrain-mitotic-onset-when-dna-54giyyvjrg.pdf

G1/S CDK is inhibited to restrain mitotic onset when DNA replication is blocked in fission yeast

The invention relates to novel antifungal compounds of formula (I). Pharmaceutical antifungal compositions for using in human medicine and veterinary science containing the compound of formula (I), wherein x is a group selected from SO- and SO2-. The compound of formula (I) used in the form of a drug and the use of said compound of formula (I) for producing a human or veterinary antifungal pharmaceutical composition are also disclosed.

1,2,4-thiadiazole derivatives antifungal compounds, compositions containing said compounds and the use thereof

The subject of the invention is an in cellulo method for screening for agents that modulate the activity of the Mdm2 ubiquitin ligase, said method comprising the following steps: a) bringing a candidate test agent into contact with recombinant yeast cells which express, in the nucleus thereof, a fusion protein comprising: (i) a polypeptide MDM2 and (ii) at least one detectable protein; b) quantifying said first detectable protein in the yeast cells, at the end of at least one predetermined period of time after the candidate agent has been brought into contact with said cells; c) comparing the value obtained in step (b) with a control value obtained when step (a) is carried out in the absence of the candidate agent.

Method for screening for agents that modulate the activity of the mdm2 ubiquitin ligase and means for implementing said method

A method for screening agents modulating IκBα protein ubiquitination by a functional ubiquitin ligase protein complex containing β-TrCP protein, the method including the following steps: (a) bringing into contact a candidate agent to be tested with recombinant yeast cells that express in their nucleus:
 (i) a fusion protein including the IκBα polypeptide and at least one first detectable protein; and (ii) a protein containing the β-TrCP polypeptide; (b) quantifying the first detectable protein in the yeast cells, at the end of at least one predetermined period of time after bringing the candidate agent into contact with the cells; (c) comparing the result obtained in step (b) with a control result obtained when step (a) is carried out in the absence of the candidate.

Method for screening agents modulating a lkb$g(a) protein ubiquitination and means for carrying out said method

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