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)

The TOR proteins are known as key regulators of cell growth in response to nutritional and mitogenic signals and as targets for the immunosuppressive and anti-cancerous drug rapamycin. The fission yeast Schizosaccharomyces pombe has two TOR homologues, tor1+ and tor2+. Despite their structural similarity, these genes have distinct functions: tor1+ is required under starvation, extreme temperatures, and osmotic or oxidative stress conditions, whereas tor2+ is required under normal growth conditions. Surprisingly, rapamycin does not seem to inhibit the S. pombe TOR-related functions. Rapamycin specifically inhibits sexual development in S. pombe, and this seems to stem from direct inhibition of the S. pombe FKBP12 homologue. Why S. pombe cells are resistant to rapamycin during the growth phase is as yet unclear and awaits further analysis of the TOR-dependent signaling pathways.
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PMID:The fission yeast TOR proteins and the rapamycin response: an unexpected tale. 1456 Sep 53

Rapamycin, a bacterial macrolide antibiotic, is a potent immunosuppressant agent that blocks cell proliferation by inhibiting the G1/S transition in several cell types. In sensitive cells, rapamycin inhibits the phosphorylation of p70 S6K and of Rb; however, the precise mechanisms involved have not been elucidated. In the mouse BP-A31 fibroblasts, synchronised in G0/G1 phase by serum starvation and induced to reinitiate the G1-phase progression, rapamycin inhibited the entry into S phase. The effect of rapamycin was situated in early G1 phase. The assembly of the cyclin D1/cdk4 complexes that phosphorylate Rb early in the G1 phase was not modified by the drug. Nevertheless, an inhibition of the activation of cyclin D1/cdk4 and cyclin E/cdk2 as well as of Rb phosphorylation accompanied the cell cycle arrest. Remarkably, rapamycin reduced the level of total p21(WAF1/CIP1) as well as that of p21(WAF1/CIP1) associated with the cyclin D1/cdk4 complexes. Besides its inhibitory activity toward cdk, p21(WAF1/CIP1) has been recently found to participate in the formation/stabilisation/nuclear translocation of cyclin D1/cdk4 complexes. We propose that the inhibition of the expression of p21(WAF1/CIP1) is a mechanism by which rapamycin inhibits the triggering of the cdk cascade in the BP-A31 cells.
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PMID:Rapamycin inhibits cdk4 activation, p 21(WAF1/CIP1) expression and G1-phase progression in transformed mouse fibroblasts. 1463 3

The recent period has witnessed progress in the understanding of the lysosomal autophagic pathway. The discovery of a family of genes conserved from yeast to humans, and involved in the formation of autophagosomes, has unraveled new protein-conjugation systems and has shed light on the importance of autophagy in physiology and pathophysiology. The elucidation of the molecular control of autophagy will also lead to a better understanding of the role of autophagy during cell death. As a great number of extracellular stimuli (starvation, hormonal or therapeutic treatment) as well as intracellular stimuli (accumulation of misfolded proteins, invasion of microorganisms) is able to modulate the autophagic response, it is not surprising that several signaling pathways are involved in the control of autophagy. The mammalian Target of Rapamycin (mTOR) signaling pathway plays a major role in transmitting autophagic stimuli because of its ability to sense nutrient, metabolic and hormonal signals. In addition, autophagy, which is characterized by a flux of membrane from the formation of the autophagosome to the fusion with the lysosome, is regulated by GTPases, similarly to the vesicular transport along the exocytic/endocytic pathway. The aim of the present review is to give an overview of autophagy and to discuss its regulation by activators and effectors of mTOR and GTPases.
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PMID:Regulation and role of autophagy in mammalian cells. 1532 84

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

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

Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTOR-targeted therapies in the treatment of advanced-stage RCC.
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PMID:Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma. 1702 98

Nutrient starvation or rapamycin treatment, through inhibition of target of rapamycin, causes condensation of ribosomal DNA (rDNA) array and nucleolar contraction in budding yeast. Here we report that under such conditions, condensin is rapidly relocated into the nucleolus and loaded to rDNA tandem repeats, which is required for rDNA condensation. Rpd3-dependent histone deacetylation is necessary and sufficient for condensin's relocalization and loading to rDNA array, suggesting that histone modification plays a regulatory role for condensin targeting. Rapamycin independently, yet coordinately, inhibits rDNA transcription and promotes condensin loading to rDNA array. Unexpectedly, we found that inhibition of rDNA transcription in the absence of condensin loading leads to rDNA instability. Our data suggest that enrichment of condensin prevents rDNA instability during nutrient starvation. Together, these observations unravel a novel role for condensin in the maintenance of regional genomic stability.
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PMID:Nutrient starvation promotes condensin loading to maintain rDNA stability. 1720 76

The rapamycin-sensitive (TOR) signalling pathway in Saccharomyces cerevisiae controls growth and cell proliferation in response to nutrient availability. Rapamycin treatment causes cells to arrest growth in G1 phase. The mechanism by which the inhibition of the TOR pathway regulates cell cycle progression is not completely understood. Here we show that rapamycin causes G1 arrest by a dual mechanism that comprises downregulation of the G1-cyclins Cln1-3 and upregulation of the Cdk inhibitor protein Sic1. The increase of Sic1 level is mostly independent of the downregulation of the G1 cyclins, being unaffected by ectopic CLN2 expression, but requires Sic1 phosphorylation of Thr173, because it is lost in cells expressing Sic1(T173A). Rapamycin-mediated Sic1 upregulation involves nuclear accumulation of a more stable, non-ubiquitinated protein. Either SIC1 deletion or CLN3 overexpression results in non-cell-cycle-specific arrest upon rapamycin treatment and makes cells sensitive to a sublethal dose of rapamycin and to nutrient starvation. In conclusion, our data indicate that Sic1 is involved in rapamycin-induced G1 arrest and that deregulated entrance into S phase severely decreases the ability of a cell to cope with starvation conditions induced by nutrient depletion or which are mimicked by rapamycin treatment.
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PMID:Rapamycin-mediated G1 arrest involves regulation of the Cdk inhibitor Sic1 in Saccharomyces cerevisiae. 1730 22

The Target of Rapamycin (TOR) protein is a Ser/Thr kinase that functions in two distinct multiprotein complexes: TORC1 and TORC2. These conserved complexes regulate many different aspects of cell growth in response to intracellular and extracellular cues. Here we report that the AGC kinase Sch9 is a substrate of yeast TORC1. Six amino acids in the C terminus of Sch9 are directly phosphorylated by TORC1. Phosphorylation of these residues is lost upon rapamycin treatment as well as carbon or nitrogen starvation and transiently reduced following application of osmotic, oxidative, or thermal stress. TORC1-dependent phosphorylation is required for Sch9 activity, and replacement of residues phosphorylated by TORC1 with Asp/Glu renders Sch9 activity TORC1 independent. Sch9 is required for TORC1 to properly regulate ribosome biogenesis, translation initiation, and entry into G0 phase, but not expression of Gln3-dependent genes. Our results suggest that Sch9 functions analogously to the mammalian TORC1 substrate S6K1 rather than the mTORC2 substrate PKB/Akt.
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PMID:Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. 1761 50

The conserved TOR (target of rapamycin) kinase is part of a TORC1 complex that regulates cellular responses to environmental stress, such as amino acid starvation and hypoxia. Dysregulation of Akt-TOR signaling has also been linked to the genesis of cancer, and thus, this pathway presents potential targets for cancer chemotherapeutics. Here we report that rapamycin-sensitive TORC1 signaling is required for the S-phase progression and viability of yeast cells in response to genotoxic stress. In the presence of the DNA-damaging agent methyl methanesulfonate (MMS), TOR-dependent cell survival required a functional S-phase checkpoint. Rapamycin inhibition of TORC1 signaling suppressed the Rad53 checkpoint-mediated induction of ribonucleotide reductase subunits Rnr1 and Rnr3, thereby abrogating MMS-induced mutagenesis and enhancing cell lethality. Moreover, cells deleted for RNR3 were hypersensitive to rapamycin plus MMS, providing the first demonstration that Rnr3 contributes to the survival of cells exposed to DNA damage. Our findings support a model whereby TORC1 acts as a survival pathway in response to genotoxic stress by maintaining the deoxynucleoside triphosphate pools necessary for error-prone translesion DNA polymerases. Thus, TOR-dependent cell survival in response to DNA-damaging agents coincides with increased mutation rates, which may contribute to the acquisition of chemotherapeutic drug resistance.
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PMID:TOR signaling is a determinant of cell survival in response to DNA damage. 1769 81


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