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)

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that modulates type I collagen synthesis. In addition, IFN-gamma also exerts potent effects on cellular tryptophan levels by inducing the expression of indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase. Because recent evidence indicates that IDO-mediated oxidative tryptophan catabolism is important in cellular responses to IFN-gamma, we investigated the role of IDO in the IFN-gamma-induced modulation of type I collagen gene expression. IFN-gamma ( > or = 50 U/ml) stimulated IDO expression in human dermal fibroblasts in vitro, resulting in a > 90% depletion of tryptophan in the culture media following incubation for 48 h. Higher concentrations of IFN-gamma ( > or = 500 U/ml) caused a marked decrease in type I collagen mRNA levels. Time-course studies indicated that maximal induction of IDO mRNA expression in IFN-gamma-treated fibroblast cultures (24 h) preceded the maximal decrease in collagen mRNA (96 h). Type I collagen mRNA levels were also markedly and selectively decreased in fibroblasts maintained in tryptophan-depleted cultures. Addition of exogenous tryptophan (up to 2500 microM) to IFN-gamma-treated fibroblasts restored "normal" concentrations of tryptophan in the culture media, but did not abrogate the IFN-gamma-induced decrease in collagen mRNA. Addition of the tryptophan metabolite kynurenine, in concentrations similar to those generated in fibroblast cultures following IFN-gamma treatment for 48 h, had no significant effect on type I collagen mRNA levels. These results indicate that although IFN-gamma causes activation of IDO and enhanced tryptophan catabolism in fibroblast cultures, neither the ensuing tryptophan starvation nor the accumulation of kynurenine in the culture media can fully account for the inhibitory effects of IFN-gamma on type I collagen mRNA expression.
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PMID:Inhibition of type I collagen mRNA expression independent of tryptophan depletion in interferon-gamma-treated human dermal fibroblasts. 766 18

The immunosuppressants cyclosporin A, FK506, and rapamycin inhibit growth of unicellular eukaryotic microorganisms and also block activation of T lymphocytes from multicellular eukaryotes. In vitro, these compounds bind and inhibit two different types of peptidyl-prolyl cis-trans isomerases. Cyclosporin A binds cyclophilins, whereas FK506 and rapamycin bind FK506-binding proteins (FKBPs). Cyclophilins and FKBPs are ubiquitous, abundant, and targeted to multiple cellular compartments, and they may fold proteins in vivo. Previously, a 12-kDa cytoplasmic FKBP was shown to be only one of at least two FK506-sensitive targets in the yeast Saccharomyces cerevisiae. We find that a second FK506-sensitive target is required for amino acid import. Amino acid-auxotrophic yeast strains (trp1 his4 leu2) are FK506 sensitive, whereas prototrophic strains (TRP1 his4 leu2, trp1 HIS4 leu2, and trp1 his4 LEU2) are FK506 resistant. Amino acids added exogenously to the growth medium mitigate FK506 toxicity. FK506 induces GCN4 expression, which is normally induced by amino acid starvation. FK506 inhibits transport of tryptophan, histidine, and leucine into yeast cells. Lastly, several genes encoding proteins involved in amino acid import or biosynthesis confer FK506 resistance. These findings demonstrate that FK506 inhibits amino acid import in yeast cells, most likely by inhibiting amino acid transporters. Amino acid transporters are integral membrane proteins which import extracellular amino acids and constitute a protein family sharing 30 to 35% identity, including eight invariant prolines. Thus, the second FK506-sensitive target in yeast cells may be a proline isomerase that plays a role in folding amino acid transporters during transit through the secretory pathway.
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PMID:The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae. 768 45

Selection-induced mutations, sometimes called "directed," "adaptive," or "Cairnsian" mutations, are spontaneous mutations that occur as specific responses to environmental challenges, usually during periods of prolonged stress, and that occur more often when they are selectively advantageous than when they are selectively neutral. In this study I show that lesions in uvrA, uvrB, uvrC, or uvrD increase the mutation rate from trpA46 to trpA+ by 10(2)- to 10(4)-fold during tryptophan starvation, but those same lesions do not affect random mutation rates in growing cells when tryptophan is present. The increased selection-induced mutation rates remain specific to the gene that is under selection in that no increase in the mutation rate from trpA46 to trpA+ is detected during proline starvation. Evidence is presented showing that proline starvation produces a state of cellular stress which results in a burst of mutations from trpA46 to trpA+ when proline-starved cells are plated onto medium lacking tryptophan but containing proline. These results are consistent with the hypermutable state model for selection-induced mutagenesis.
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PMID:Genetics of selection-induced mutations: I. uvrA, uvrB, uvrC, and uvrD are selection-induced specific mutator loci. 771 15

On amino acid starvation, Escherichia coli cells exhibit an adaptive facility termed the stringent response. This is characterized by the production of high levels of a regulatory nucleotide, ppGpp, and concomitant curtailment in rRNA synthesis. Various studies reported earlier indicated that RNA polymerase is the site of action of ppGpp although a direct demonstration of the interaction of ppGpp with E. coli RNA polymerase is still lacking. Here we report the labelling of ppGpp with a fluorescent probe, 1-aminonapthalene-5-sulphonate (AmNS), at the terminal phosphates. AmNS-ppGpp responded much like a ppGpp molecule in an in vitro total transcription assay at selective promoters. Fluorescence titration of the tryptophan emission of RNA polymerase by AmNS-ppGpp indicated a unique binding site in the absence of template DNA. Competition experiments showed that unlabelled ppGpp binds to the enzyme at the same site. Sigma factor seems to have no effect on this binding. The titration profile is also characterized by a single slope in the Scatchard analysis. The presence of GTP or GDP does not influence the binding of AmNS-ppGpp with RNA polymerase. Forster's distance measurement was carried out which placed AmNS-ppGpp 27 A away from the rifampicin-binding domain of RNA polymerase.
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PMID:Evidence for a ppGpp-binding site on Escherichia coli RNA polymerase: proximity relationship with the rifampicin-binding domain. 774 47

A full-length cDNA clone for rat asparagine synthetase (AS) was isolated from a cDNA library enriched for amino acid-regulated sequences. The AS cDNA was used to investigate the amino acid-dependent repression of AS mRNA content in rat Fao hepatoma cells. In response to complete amino acid starvation, there was an approximately 10-fold increase in the level of AS mRNA. Three species of mRNA, of approx. sizes 2.0, 2.5 and 4.0 kb, were detected and each was simultaneously regulated to the same degree. The expression of AS mRNA increased by 6 h after removal of amino acids, reached a plateau after 9 h, and was blocked by either actinomycin D or cycloheximide. Partial repression of the AS mRNA content was maintained by the presence of a single amino acid in the culture medium, but the degree of effectiveness for each one varied widely. Glutamine showed the greatest ability to repress the AS mRNA content, even at an extracellular concentration 10 times below its plasma level. Other effective repressors included the amino acids asparagine, histidine and leucine, as well as ammonia. Depletion of selected single amino acids from an otherwise complete culture medium also caused up-regulation. In particular, removal of histidine, threonine or tryptophan from the medium, or the addition of histidinol to inhibit histidinyl-tRNA synthetase, resulted in a significant increase in AS mRNA content. The data indicate that nutrient regulation of AS mRNA occurs by a general control mechanism that is responsive to a spectrum of amino acids.
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PMID:Cloning of rat asparagine synthetase and specificity of the amino acid-dependent control of its mRNA content. 781 76

Saccharomyces cerevisiae mutant E124 was selected in a visual screen based on elongated cell shape. Genetic analysis showed that E124 contains two separate mutations, pps1-1 and elm4-1, each causing a distinct phenotype inherited as a single-gene trait. In rich medium, pps1-1 by itself causes increased doubling time but does not affect cell shape, whereas elm4-1 results in a moderate cell elongation phenotype but does not affect growth rate. Reconstructed elm4-1 pps1-1 double mutants display a synthetic phenotype in rich medium including extreme cell elongation and delayed cell separation, both characteristics of pseudohyphal differentiation. The elm4-1 mutation was shown to act as a dominant factor that potentiates pseudohyphal differentiation in response to general nitrogen starvation in a genetic background in which pseudohyphal growth normally does not occur. Thus, elm4-1 allows recognition of, or response to, a pseudohyphal differentiation signal that results from nitrogen limitation. PPS1 was isolated and shown to be a previously undescribed gene coding for a protein similar in amino acid sequence to phosphoribosylpyrophosphate synthase, a rate-limiting enzyme in the biosynthesis of nucleotides, histidine, and tryptophan. Thus, the pps1-1 mutation may generate a nitrogen limitation signal, which when coupled with elm4-1 results in pseudohyphal growth even in rich medium.
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PMID:The Saccharomyces cerevisiae mutation elm4-1 facilitates pseudohyphal differentiation and interacts with a deficiency in phosphoribosylpyrophosphate synthase activity to cause constitutive pseudohyphal growth. 800 70

A tryptophan-auxotrophic mutant of the archaeon Methanobacterium thermoautotrophicum Marburg was grown with growth-promoting and growth-limiting concentrations of tryptophan. The specific activities of anthranilate synthase (TrpEG) and tryptophan synthase (TrpB) increased 30- to 40-fold in tryptophan-starved cells. Levels of trpE-specific and trpD-specific mRNAs (transcripts of the first and the last genes, respectively, of the M. thermoautotrophicum Marburg trp gene cluster) increased about 10-fold upon starvation for tryptophan. Thus, the expression of the trp genes appears to be regulated primarily at the level of transcription. These data support transcription of trp genes as an operon and support a regulatory model involving a repressor. Anthranilate synthase was feedback inhibited by L-tryptophan, with a Ki of 3.0 microM. In a leucine-auxotrophic mutant starved for L-leucine, the level of alpha-isopropylmalate synthase (LeuA) was 10-fold higher than in cells grown with L-leucine. In addition to the finding of specific regulation of gene expression by the end products of their respective pathways, it was found that the levels of anthranilate synthase and alpha-isopropylmalate synthase were reduced upon growth in the presence of amino acids of other families, such as L-alanine, L-proline, or L-arginine. Conversely, starvation for tryptophan caused a slight elevation of alpha-isopropylmalate synthase and starvation for leucine caused a significant increase of anthranilate synthase and tryptophan synthase specific activities. The latter effect was also observed at the level of trp-specific mRNA and is reminiscent of general amino acid control.
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PMID:Regulation of tryptophan biosynthesis in Methanobacterium thermoautotrophicum Marburg. 804 89

In the thermophilic archaeon Methanobacterium thermoautotrophicum Marburg, the structural gene for isoleucyl-tRNA synthetase (ileS) is flanked upstream by orf401 and downstream by purL. orf401 encodes a 43.5-kDa protein with an unknown function. Northern (RNA) hybridization and S1 nuclease protection experiments showed that the orf401, ileS, and purL genes are cotranscribed from an archael consensus promoter in front of orf401. The corresponding transcript was about eightfold increased in cells that had been exposed to pseudomonic acid A, a specific inhibitor of isoleucyl-tRNA synthetase. Growth inhibition by puromycin, tryptophan starvation, or starvation for hydrogen did not affect the level of this transcript. The level of a trpE transcript, however, was drastically elevated upon tryptophan starvation, while inhibition by pseudomonic acid A had no effect on the level of this transcript. Expression of ileS thus appears to be controlled by a regulatory mechanism which specifically responds to the availability of isoleucyl-tRNA. Extensive decay of the orf401-ileS-purL message was observed. Degradation occurred, presumably by endonucleolytic cleavage, within the orf401 region.
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PMID:Transcription of the ileS operon in the archaeon Methanobacterium thermoautotrophicum Marburg. 837 40

Total blood and plasma free amino acids and plasma urea levels were studied in fed and 24 h fasted Zucker rats. In fed animals there were no differences between obese and lean rats in the overall essential and non essential blood free amino acids. However, starvation reduced blood amino acid levels in the obese animals compared to the lean group, mainly due to changes in the plasma compartment. The reduction of available amino acids from plasma in the obese rats during starvation affected most of the amino acids, including the branched chain amino acids, which showed higher levels in the fed situation than in lean rats. Of particular interest is the opposite response to starvation in lean and obese Zucker rats concerning the plasma ratio of tryptophan (Trp) to the large neutral amino acids (LNAA) which could be implicated in the alteration of food intake and energy expenditure characteristic of obesity.
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PMID:Opposite response to starvation of Trp/LNAA ratio in lean and obese Zucker rats. 848 65

Phosphoribosyl diphosphate-lacking (delta prs) mutant strains of Escherichia coli require NAD, guanosine, uridine, histidine, and tryptophan for growth. NAD is required by phosphoribosyl diphosphate-lacking mutants because of lack of one of the substrates for the quinolinate phosphoribosyltransferase reaction, an enzyme of the NAD de novo pathway. Several NAD-independent mutants of a host from which prs had been deleted were isolated; all of them were shown to have lesions in the pstSCAB-phoU operon, in which mutations lead to derepression of the Pho regulon. In addition NAD-independent growth was dependent on a functional quinolinate phosphoribosyltransferase. The prs suppressor mutations led to the synthesis of a new phosphoryl compound that may act as a precursor for a new NAD biosynthetic pathway. This compound may be synthesized by the product of an unknown phosphate starvation-inducible gene of the Pho regulon because the ability of pst or phoU mutations to suppress the NAD requirement requires PhoB, the transcriptional activator of the Pho regulon.
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PMID:Phosphoribosyl diphosphate synthetase-independent NAD de novo synthesis in Escherichia coli: a new phenotype of phosphate regulon mutants. 855 May 5


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