Molecular basis of cyclin-CDK-CKI regulation by reversible binding of an inositol pyrophosphate

Lee, Young‐Sam; Huang, Kexin; Quiocho, Florante A.; O’Shea, Erin K.

doi:10.1038/nchembio.2007.52

Cited by 151 publications

(200 citation statements)

References 35 publications

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“…Consistently, IP7 was more abundant in cells under low-phosphate conditions, and Pho4 localization was reduced or elevated, respectively, by mutations impairing IP7 synthesis (vip1) or degradation (ddp1) (Figure 6) (Lee et al 2007). Since Pho81 constitutively interacts with the Pho80-Pho85 kinase complex, IP7 is thought to reversibly change Pho81 conformation and affect accessibility of the kinase substrate (Lee et al 2008). Although several earlier reports, including transcriptome analyses, had linked insositol phosphate metabolism with the phosphate response (Flick and Thorner 1998;El Alami et al 2003;Steger et al 2003;Auesukaree et al 2005), the results were not entirely consistent.…”

Section: Role Of An Intermediate Metabolite (Ip7) In the Regulation Ocontrasting

confidence: 51%

Regulation of Amino Acid, Nucleotide, and Phosphate Metabolism in Saccharomyces cerevisiae

2012

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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.

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Section: Role Of An Intermediate Metabolite (Ip7) In the Regulation Ocontrasting

confidence: 51%

Regulation of Amino Acid, Nucleotide, and Phosphate Metabolism in Saccharomyces cerevisiae

2012

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“…However, HXK2 mutants are deficient for glucose repression (23), as is another candidate, ⌬REG1, a regulator of the protein phosphatase type 1 (PP1; GLC7) (24). Moreover, the identified cyclin PCL8 interacts with the Cdk Pho85, which itself phosphorylates the PP1 regulator Glc8 (25,26). Taken together, these findings suggest that the prevention of glucose repression mediates 2-DG resistance, indicating that 2-DG-mediated growth inhibition is a regulatory consequence.…”

Section: Resultsmentioning

confidence: 51%

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

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Struys

et al. 2008

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

149

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The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.cell growth inhibition ͉ glycolysis ͉ off-target effect ͉ pentose phosphate pathway ͉ carbohydrate metabolism 2 -Deoxy-D-glucose (2-DG) is a stable glucose analogue that is actively taken up by the hexose transporters and phosphor ylated but cannot be fully metabolized. 2-DG-6-phosphate accumulates in the cell and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes. 2-DG-6-phosphate inhibits phosphoglucose isomerase (PGI) in a competitive, and hexokinase (HXK) in a noncompetitive, manner (1-3). On the cellular level, 2-DG provokes rapid growth inhibition and results in altered glycosylation that is highly dependent on catabolic glucose intermediates (4, 5).2-DG has been used in numerous studies focused on the effects of reduced metabolic rates. Recently, 2-DG has been used in this study of glycolytic inhibition with respect to calorie restriction and aging. 2-DG increases the lifespan of C. elegans, an effect that is reversed by antioxidants (6, 7). Moreover, 2-DG mitigates disease progression in a murine model of temporal lobe epilepsy (8), possibly due to the repression of the BDNF promoter. 2-DG shows possibilities as an antiviral drug, as it targets gene expression in papillomavirus (9). Finally, 2-DG has been thoroughly studied in regard to cancer biology. Malignant cells exhibit increased glucose metabolism compared with surrounding tissue (10) and, therefore, increased 2-DG uptake. 2-DG efficiently inhibits tumor progression and is a focus of clinical trials (reviewed in ref. 11).In general, it is assumed that the biological effects of 2-DG are the consequence of a block in carbohydrate catalysis, implying that 2-DG treated cells, unable to metabolize glucose, stop growing as a result of a lack of energy and metabolic intermediates. However, several observations bring this assumption into question. First, only a moderate decline in ATP has been observed in 2-DG-treated eukaryotes (7,12). Second, a current study reveals that tumor cells react differently to 2-DG than to its close analogue 2-fluorod...

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“…Recent evidence shows that inositol polyphosphate species play a particular role in this regulation. More specifically, isoform synthesized by Vip1 was found to bind non-covalently with Pho80-Pho85-Pho81, thereby inducing additional interactions between Pho81 and Pho80-Pho85 that prevent substrates from accessing the kinase active site (Lee et al 2007;Lee et al 2008b). Intriguingly, under phosphate starvation conditions, Pho4-dependent antisense and intragenic RNA transcription in the KCS1 locus induces downregulation of the Kcs1 activity, leading to a positive feedback loop for activation of the PHO genes (Nishizawa et al 2008a).…”

Section: The Protein Kinase Sch9mentioning

confidence: 99%

“…In contrast, the control of Rim15-dependent phenotypes requires fulllength Pho81, providing evidence that Pho81 is able to discriminate between different effectors of the same Pho85-Pho80 kinase (Swinnen et al 2005). The molecular mechanism underlying this discrimination is still largely elusive, but several phosphorylation sites on Pho81 (Knight et al 2004) and an involvement of inositol polyphosphates (Lee et al 2008b) could be essential.…”

Section: The Protein Kinase Sch9mentioning

confidence: 99%

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

et al. 2010

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Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G 0 ) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.

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Molecular basis of cyclin-CDK-CKI regulation by reversible binding of an inositol pyrophosphate

Cited by 151 publications

References 35 publications

Regulation of Amino Acid, Nucleotide, and Phosphate Metabolism in Saccharomyces cerevisiae

Regulation of Amino Acid, Nucleotide, and Phosphate Metabolism in Saccharomyces cerevisiae

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

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