Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to starvation, eukaryotic cells recover nutrients through autophagy, a lysosomal-mediated process of cytoplasmic degradation. Autophagy is known to be inhibited by TOR signaling, but the mechanisms of autophagy regulation and its role in TOR-mediated cell growth are unclear. Here, we show that signaling through TOR and its upstream regulators PI3K and Rheb is necessary and sufficient to suppress starvation-induced autophagy in the Drosophila fat body. In contrast, TOR's downstream effector S6K promotes rather than suppresses autophagy, suggesting S6K downregulation may limit autophagy during extended starvation. Despite the catabolic potential of autophagy, disruption of conserved components of the autophagic machinery, including ATG1 and ATG5, does not restore growth to TOR mutant cells. Instead, inhibition of autophagy enhances TOR mutant phenotypes, including reduced cell size, growth rate, and survival. Thus, in cells lacking TOR, autophagy plays a protective role that is dominant over its potential role as a growth suppressor.
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PMID:Role and regulation of starvation-induced autophagy in the Drosophila fat body. 1529 10

In the yeast Saccharomyces cerevisiae, the zinc finger transcription factor Msn2p is a central component of the general stress response. It is activated in response to a wide variety of environmental changes, including physicochemical stresses as well as nutritional starvation, and induces the expression of a large set of genes required for cellular adaptation. The transcriptional activity of Msn2p in response to stresses is transient, and must therefore be strictly controlled. It is mainly regulated by reversible translocation from the cytoplasm to the nucleus upon the onset of stress, under the control of the cAMP-APK and the TOR pathways. In this report, we describe a new level of control: heat shock-induced degradation of Msn2p by the 26S proteasome. This degradation occurs in the nucleus and is further enhanced when Msn2p is fully active. Moreover, we show that the cyclin-dependent protein kinase Srb10p, a component of the transcription machinery, plays a role in the enhanced degradation of Msn2p upon heat shock. These findings provide new insights into the mechanisms by which Msn2p is transiently activated in response to stress.
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PMID:Heat shock-induced degradation of Msn2p, a Saccharomyces cerevisiae transcription factor, occurs in the nucleus. 1537 96

Cell-size homeostasis entails a fundamental balance between growth and division. The budding yeast Saccharomyces cerevisiae establishes this balance by enforcing growth to a critical cell size prior to cell cycle commitment (Start) in late G1 phase. Nutrients modulate the critical size threshold, such that cells are large in rich medium and small in poor medium. Here, we show that two potent negative regulators of Start, Sfp1 and Sch9, are activators of the ribosomal protein (RP) and ribosome biogenesis (Ribi) regulons, the transcriptional programs that dictate ribosome synthesis rate in accord with environmental and intracellular conditions. Sfp1 and Sch9 are required for carbon-source modulation of cell size and are regulated at the level of nuclear localization and abundance, respectively. Sfp1 nuclear concentration responds rapidly to nutrient and stress conditions and is regulated by the Ras/PKA and TOR signaling pathways. In turn, Sfp1 influences the nuclear localization of Fhl1 and Ifh1, which bind to RP gene promoters. Starvation or the absence of Sfp1 causes Fhl1 and Ifh1 to localize to nucleolar regions, concomitant with reduced RP gene transcription. These findings suggest that nutrient signals set the critical cell-size threshold via Sfp1 and Sch9-mediated control of ribosome biosynthetic rates.
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PMID:A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. 1546 58

TOR protein kinases are key regulators of cell growth in eukaryotes. TOR is also known as the target protein for the immunosuppressive and potentially anticancer drug rapamycin. The fission yeast Schizosaccharomyces pombe has two TOR homologs. tor1+ is required under starvation and a variety of stresses, while tor2+ is an essential gene. Surprisingly, to date no rapamycin-sensitive TOR-dependent function has been identified in S. pombe. Herein, we show that S. pombe auxotrophs, in particular leucine auxotrophs, are sensitive to rapamycin. This sensitivity is suppressed by deletion of the S. pombe FKBP12 or by introducing a rapamycin-binding defective tor1 allele, suggesting that rapamycin inhibits a tor1p-dependent function. Sensitivity of leucine auxotrophs to rapamycin is observed when ammonia is used as the nitrogen source and can be suppressed by its replacement with proline. Consistently, using radioactive labeled leucine, we show that cells treated with rapamycin or disrupted for tor1+ are defective in leucine uptake when the nitrogen source is ammonia but not proline. Recently, it has been reported that tsc1+ and tsc2+, the S. pombe homologs for the mammalian TSC1 and TSC2, are also defective in leucine uptake. TSC1 and TSC2 may antagonize TOR signaling in mammalian cells and Drosophila. We show that reduction of leucine uptake in tor1 mutants is correlated with decreased expression of three putative amino acid permeases that are also downregulated in tsc1 or tsc2. These findings suggest a possible mechanism for regulation of leucine uptake by tor1p and indicate that tor1p, as well as tsc1p and tsc2p, positively regulates leucine uptake in S. pombe.
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PMID:Regulation of leucine uptake by tor1+ in Schizosaccharomyces pombe is sensitive to rapamycin. 1546 17

The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment, respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)P2, suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer.
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PMID:Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. 1553 61

Regulation of ribosome biogenesis is central to the control of cell growth. In rapidly growing yeast cells, ribosomal protein (RP) genes account for approximately one-half of all polymerase II transcription-initiation events, yet these genes are markedly and coordinately downregulated in response to a number of environmental stress conditions, or during the transition from fermentation to respiration. Although several conserved signalling pathways (TOR, RAS/protein kinase A and protein kinase C) impinge upon RP gene transcription, little is known about how initiation at these genes is controlled. Rap1 (refs 6, 7) and more recently Fhl1 (ref. 8) were shown to bind upstream of many RP genes. Here we show that the essential protein Ifh1 binds to and activates many RP gene promoters under optimal growth conditions in Saccharomyces cerevisiae. Ifh1 is recruited to RP gene promoters through the forkhead-associated domain of Fhl1. Ifh1 binding decreases when RP genes are downregulated either by TOR inhibition or nutrient depletion, and is restored after release from starvation or upon regulated induction of IFH1 expression. These findings indicate a central role for Ifh1 and Fhl1 in RP gene regulation.
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PMID:Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1. 1561 69

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy that is conserved throughout eukaryotes. It is activated by rising AMP, signifying falling energy status caused by starvation for a carbon source or other stress. Binding of AMP to the regulatory gamma subunit triggers phosphorylation of the catalytic alpha subunit by the upstream kinase LKB1, and the activated kinase switches on ATP-generating catabolic pathways while switching off ATP-requiring processes. AMPK inhibits the TOR (target of rapamycin) pathway by phosphorylating TSC2, thus inhibiting cell growth during times of stress. AMPK is also a target for adipokines that regulate energy balance at the whole-body level.
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PMID:New roles for the LKB1-->AMPK pathway. 1578 May 93

The fruit fly Drosophila is a useful organism for the investigation of the mechanisms by which dietary restriction (DR) extends lifespan. Its relatively short generation time, well-characterised molecular biology, genetics and physiology and ease of handling for demographic analysis are all major strengths. Lifespan has been extended by DR applied to adult Drosophila, by restriction of the availability of live yeast or by co-ordinate dilution of the whole food medium. Lifespan increases to a maximum through DR with a progressive dilution of the food and then decreases through starvation as the food is diluted further. Daily and lifetime fecundities of females are reduced by food dilution throughout the DR and starvation range. Standard Drosophila food ingredients differ greatly between laboratories and fly stocks can differ in their responses to food dilution, and a full range of food concentrations should therefore be investigated when examining the response to DR. Flies do not alter the time that they spend feeding in response to DR. Both mean and maximum lifespan are extended by DR. The nutrients critical for the response to DR in Drosophila require definition. The extension of lifespan in response to DR is very much greater in females than in males. Two nutrient-sensing pathways, the insulin/IGF-like and TOR pathways, have been implicated in mediating this response of lifespan to DR in Drosophila, as have two protein deacetylases, dSir2 and Rpd3, although the precise nature of this interaction remain to be characterised. Although female fecundity is reduced by DR, the response of lifespan to DR appears normal in sterile females, possibly implying that reduced fecundity is not necessary for extension of lifespan by DR. There is no reduction in metabolic rate or in the rate of generation of superoxide and hydrogen peroxide from isolated mitochondria in response to DR. DR acts acutely and rapidly (within 48 h) to reduce the mortality of flies that are fully fed to the level found in animals exposed to DR throughout life. This rapid mortality rate recovery provides a powerful framework within which to further investigate the mechanisms by which DR extends lifespan.
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PMID:Dietary restriction in Drosophila. 1593 41

Saccharomyces cerevisiae growing exponentially in anaerobic batch cultures that are suddenly exposed to carbon starvation will rapidly lose almost all ATP. This will cause an energy deficiency and adaptation to starvation conditions is prohibited. As a result, viability and fermentative capacity will be drastically reduced during prolonged starvation. However, if the cells are incubated in the presence of rapamycin (which will inactivate the TOR pathway) before carbon starvation ATP levels, viability and fermentative capacity will be preserved to a much larger extent compared to untreated cells. The beneficial effect of rapamycin cannot be explained by induction of a stationary phase phenotype. In fact, under these anaerobic well-controlled growth conditions, rapamycin-treated cells were still metabolically active and continued to grow, albeit not exponentially and with a reduced protein content. It is hypothesized that the loss of ATP during carbon starvation occurs because protein synthesis does not make an immediate arrest at the onset of starvation. Since there are no external or internal energy sources, this will rapidly deplete the cells of ATP. Rapamycin-treated cells, on the other hand, have already downregulated the protein-synthesizing machinery and are thus better suited to cope with a sudden carbon starvation condition. This hypothesis is strengthened by the fact that treating the cells with the protein synthesis inhibitor cycloheximide also improves the carbon starvation tolerance, although not to the same extent as rapamycin. The even better effect of rapamycin is explained by accumulation of storage carbohydrates, which is not observed for cycloheximide-treated cells.
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PMID:Rapamycin pre-treatment preserves viability, ATP level and catabolic capacity during carbon starvation of Saccharomyces cerevisiae. 1603 23

Chronological life span (CLS) in Saccharomyces cerevisiae, defined as the time cells in a stationary phase culture remain viable, has been proposed as a model for the aging of post-mitotic tissues in mammals. We developed a high-throughput assay to determine CLS for approximately 4800 single-gene deletion strains of yeast, and identified long-lived strains carrying mutations in the conserved TOR pathway. TOR signaling regulates multiple cellular processes in response to nutrients, especially amino acids, raising the possibility that decreased TOR signaling mediates life span extension by calorie restriction. In support of this possibility, removal of either asparagine or glutamate from the media significantly increased stationary phase survival. Pharmacological inhibition of TOR signaling by methionine sulfoximine or rapamycin also increased CLS. Decreased TOR activity also promoted increased accumulation of storage carbohydrates and enhanced stress resistance and nuclear relocalization of the stress-related transcription factor Msn2. We propose that up-regulation of a highly conserved response to starvation-induced stress is important for life span extension by decreased TOR signaling in yeast and higher eukaryotes.
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PMID:Extension of chronological life span in yeast by decreased TOR pathway signaling. 1641 83


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