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 rapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth program in response to nutrients such as nitrogen and carbon. The TOR1 and TOR2 kinases (TOR) control cytoplasmic protein synthesis and degradation through the conserved TAP42 protein. Upon phosphorylation by TOR, TAP42 binds and possibly inhibits type 2A and type-2A-related phosphatases; however, the mechanism by which TOR controls nuclear events such as global repression of starvation-specific transcription is unknown. Here we show that TOR prevents transcription of genes expressed upon nitrogen limitation by promoting the association of the GATA transcription factor GLN3 with the cytoplasmic protein URE2. The binding of GLN3 to URE2 requires TOR-dependent phosphorylation of GLN3. Phosphorylation and cytoplasmic retention of GLN3 are also dependent on the TOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4. TOR inhibits expression of carbon-source-regulated genes by stimulating the binding of the transcriptional activators MSN2 and MSN4 to the cytoplasmic 14-3-3 protein BMH2. Thus, the TOR signalling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm.
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PMID:The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. 1060 78

Phosphorylation of the Bad protein is a key regulatory event in the prevention of apoptosis by survival factors. Phosphorylated Bad binds to the cytosolic 14-3-3 protein and is sequestered from the apoptotic machinery of the mitochondrial membrane. To examine the role of Bad in cell growth and apoptosis in primary cultures, we produced stable Bad transfectants of chicken embryo fibroblasts (CEF). As expected, serum starvation of Bad transfectants promoted apoptosis. However, Bad-transfected CEF maintained in media with a high serum concentration were capable of anchorage-independent growth and grew to a higher saturation density than control CEF transfected with the empty vector. High dilutions of the infectious retroviral vector RCAS expressing Bad led to the formation of multilayered cell foci. The growth-promoting effects of Bad were dependent on the serine 136 phosphorylation site and correlated directly with binding of Bad to 14-3-3. These results suggest that phosphorylated Bad promotes cell growth and in oncogenic transformation may contribute to the neoplastic phenotype of the cell.
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PMID:The growth-promoting activity of the Bad protein in chicken embryo fibroblasts requires binding to protein 14-3-3. 1152 96

14-3-3 proteins bind to phosphorylated proteins and regulate a variety of cellular activities as effectors of serine/threonine phosphorylation. To define processes requiring 14-3-3 function in yeast, mutants with increased sensitivity to reduced 14-3-3 protein levels were identified by synthetic lethal screening. One mutation was found to be allelic to YPK1, which encodes a Ser/Thr protein kinase. Loss of Ypk function causes hypersensitivity to rapamycin, similar to 14-3-3 mutations and other mutations affecting the TOR signaling pathway in yeast. Similar to treatment with rapamycin, loss of Ypk function disrupted translation, at least in part by causing depletion of eIF4G, a central adaptor protein required for cap-dependent mRNA translation initiation. In addition, Ypk1 as well as eIF4G protein levels were rapidly depleted upon nitrogen starvation, but not during glucose starvation, even though both conditions inhibit translation initiation. These results suggest that Ypk regulates translation initiation in response to nutrient signals, either through the TOR pathway or in a functionally related pathway parallel to TOR.
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PMID:Loss of ypk1 function causes rapamycin sensitivity, inhibition of translation initiation and synthetic lethality in 14-3-3-deficient yeast. 1219 92

In the simple metazoan Hydra a clear link between food supply and cell survival has been established. Whilst in plants 14-3-3 proteins are found to be involved in signalling cascades that regulate metabolism, in animals they have been shown to participate in cell survival pathways. In order to explore the possibility that 14-3-3 proteins in Hydra could be involved in regulating metabolism under different conditions of food supply, we have cloned two isoforms of 14-3-3 proteins. We show here that 14-3-3 proteins bind to phosphorylated targets in Hydra and form homo- and heterodimers in vitro. 14-3-3 proteins are localised in the cytoplasm of all cells and also in the nuclei of some epithelial cells. This nuclear localisation becomes more prominent during starvation. Moreover, 14-3-3 protein is present in large amounts in food granules and from this we conclude that it performs functions which are associated with metabolism and food storage in Hydra.
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PMID:Molecular cloning and cellular distribution of two 14-3-3 isoforms from Hydra: 14-3-3 proteins respond to starvation and bind to phosphorylated targets. 1268 Dec 83

In response to stress and nutrient starvation, the Saccharomyces cerevisiae transcription factor Msn2p accumulates in the nucleus and activates expression of a broad array of genes. Here, we analyze the role of the Tor (target of rapamycin) signaling pathway in mediating these responses. Inactivation of the Tor pathway component Tap42p using tap42(Ts) alleles causes a sustained nuclear localization similar to that after the addition of the Tor kinase inhibitor rapamycin. Effects of Tap42p inactivation and rapamycin addition could be suppressed by deletion of TIP41, which encodes a Tap42p-interacting protein. These results support the notion that rapamycin affects Msn2p by inactivating Tap42p function. Tap42p interacts with the catalytic subunit of PP2A (protein phosphatase 2A) and PP2A-like phosphatases. Deletion of either the catalytic or regulatory subunit that forms the PP2A phosphatase complex prevents nuclear accumulation of Msn2p in the tap42(Ts) strain and in wild-type strains treated with rapamycin. These results suggest that Tap42p is an inhibitor of PP2A phosphatase, which in turn inhibits nuclear export of Msn2p. Interestingly, PP2A function is also required for nuclear accumulation of Msn2p in response to stresses, such as heat and osmotic shock, as well as nitrogen (but not glucose) starvation. Thus, PP2A and the Tor kinase pathway transduce stress and nitrogen starvation signals to Msn2p. Finally, Msn2p localization is unaffected by conditional loss of 14-3-3 protein function, ruling out the possibility that 14-3-3 proteins act as a scaffold to sequester Msn2p in the cytoplasm.
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PMID:PP2A phosphatase activity is required for stress and Tor kinase regulation of yeast stress response factor Msn2p. 1547 Feb 55

Overexpression of even non-toxic proteins in bacteria causes a starvation-like response: the arrest of bacterial proliferation and apoptotic-like suicidal cell death. We have shown here that, as in the cells of higher organisms, these effects are accompanied by DNA degradation. The fusion with the bacterial MBP of a polypeptide, belonging to the 14-3-3 family and normally expressed in pumpkin (C. pepo), modifies the apoptotic-like effects of overexpression of this protein in E. coli. Fusion of the full length 14-3-3 protein with the MBP considerably slows down the DNA degradation caused by overexpression of the unmodified MBP. Overexpression of the construct containing a truncated version of the 14-3-3 polypeptide causes immediate arrest of bacterial growth and rapid degradation of the chromosomal DNA. This result suggests that the DNA degradation in bacteria is an active process which can be modified to some extent by an endogenous protein.
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PMID:Modification of the apoptotic-like effects of MBP protein overexpression in E. coli by fusion with 14-3-3 derived polypeptides. 1646 40

Fission yeast requires nutritional starvation to switch the mitotic cell cycle to sexual differentiation, but sam mutants, of which we had isolated nine alleles, mate without the starvation condition. These mutants are useful for understanding the mechanism underlying the way cells sense nutritional starvation and change the cell cycle. To identify the sam allele, we first sought phenotypes other than the original sam phenotype. We found that all nine sam mutants were sensitive to 1 M KCl, that sam2, sam3, sam4 and sam9 were sensitive to 0.1 M CaCl(2), and that only the sam4 mutant was sensitive to 150 J/m(2) UV. This peculiar phenotype of sam4 suggested to us that sam4 might be an allele of rad24, which encodes a 14-3-3 protein. In fact, the Rad24 protein disappeared in sam4 and the rad24 mRNA was not transcribed in sam4. In addition, the mutation that changed Gln to a stop codon was found in the rad24 locus of sam4. Hence we concluded that sam4 is an allele of rad24. We also found that over-expression of rad24 or rad25 (a paralog of rad24) has a suppressive effect on sam1, and that sam1 was not an allele of rad24 nor rad25. Thus 14-3-3 proteins are deeply involved in the switching of the mitotic cell cycle to the sexual differentiation of fission yeast.
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PMID:Identification of sam4 as a rad24 allele in Schizosaccharomyces pombe. 1958 44

Germination followed by seedling growth constitutes two essential steps in the initiation of a new life cycle in plants, and in cereals, completion of these steps is regulated by sugar starvation and the hormone gibberellin. A calcium-dependent protein kinase 1 gene (OsCDPK1) was identified by differential screening of a cDNA library derived from sucrose-starved rice suspension cells. The expression of OsCDPK1 was found to be specifically activated by sucrose starvation among several stress conditions tested as well as activated transiently during post-germination seedling growth. In gain- and loss-of-function studies performed with transgenic rice overexpressing a constitutively active or RNA interference gene knockdown construct, respectively, OsCDPK1 was found to negatively regulate the expression of enzymes essential for GA biosynthesis. In contrast, OsCDPK1 activated the expression of a 14-3-3 protein, GF14c. Overexpression of either constitutively active OsCDPK1 or GF14c enhanced drought tolerance in transgenic rice seedlings. Hence, our studies demonstrated that OsCDPK1 transduces the post-germination Ca(2+) signal derived from sugar starvation and GA, refines the endogenous GA concentration and prevents drought stress injury, all essential functions to seedling development at the beginning of the life cycle in rice.
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PMID:Sugar starvation- and GA-inducible calcium-dependent protein kinase 1 feedback regulates GA biosynthesis and activates a 14-3-3 protein to confer drought tolerance in rice seedlings. 2332 72

14-3-3 proteins are implicated in the regulation of proteins involved in a variety of signaling pathways. 14-3-3-dependent protein regulation occurs through phosphorylation-dependent binding that results, in many cases, in the release of survival signals in cells. Autophagy is a cell digestion process that contributes to overcoming nutrient deprivation and is initiated under stress conditions. However, whether autophagy is a cell survival or cell death mechanism remains under discussion and may depend on context. Nevertheless, autophagy is a cellular process that determines cell fate and is tightly regulated by different signaling pathways, some of which, for example MAPK, PI3K and mTOR, are tightly regulated by 14-3-3 proteins. It is therefore important to understand the role of 14-3-3 protein in modulating the autophagic process. Within this context, direct binding of 14-3-3 to mTOR regulatory proteins, such as TSC2 and PRAS40, connects 14-3-3 with autophagy regulatory processes. In addition, 14-3-3 binding to human vacuolar protein sorting 34 (hVps34), a class III phosphatidylinositol-3-kinase (PI3KC3), indicates the involvement of 14-3-3 proteins in regulating autophagosome formation. hVps34 is involved in vesicle trafficking processes such as autophagy, and its activation is needed for initiation of autophagy. Chromatography and overlay techniques suggest that hVps34 directly interacts with 14-3-3 proteins under physiological conditions, thereby maintaining hVps34 in an inactive state. In contrast, nutrient starvation promotes dissociation of the 14-3-3–hVps34 complex, thereby enhancing hVps34 lipid kinase activity. Thus, 14-3-3 proteins are regulators of autophagy through regulating key components of the autophagic machinery. This review summarizes the role of 14-3-3 protein in the control of target proteins involved in regulating the master switches of autophagy.
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PMID:14-3-3 Proteins are Regulators of Autophagy. 2471 May 29

Nitrogen is an essential macronutrient for plant growth and crop productivity. The aim of this work was to further investigate the molecular events during plant adaptation to nitrogen stress. Here, we present a SWATH-MS (Sequential window acquisition of all theoretical mass spectra)-based quantitative approach to detect proteome changes in Arabidopsis seedlings following nitrogen starvation. In total, 736 proteins of diverse functions were determined to show significant abundance changes between nitrogen-supplied and nitrogen-starved Arabidopsis seedlings. Functional categorization revealed the involvement of nitrogen stress-responsive proteins in biological processes including amino acid and protein metabolism, photosynthesis, lipid metabolism and glucosinolate metabolism. Subsequent phospholipid profiling of Arabidopsis seedlings showed changes in phospholipid composition that may enhance membrane fluidity as a response to nitrogen starvation. Moreover, an Arabidopsis grf6 T-DNA insertion mutant was found to have a nitrogen stress-sensitive phenotype. GRF6 is a 14-3-3 protein with elevated abundance upon nitrogen starvation and it may function as a positive regulator during nitrogen stress adaptation.
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PMID:SWATH-MS quantitative proteomic investigation of nitrogen starvation in Arabidopsis reveals new aspects of plant nitrogen stress responses. 3004 75


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