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)

Changes in the patterns of isoacceptors of tRNAAsn and alterations in modification of the guanine residue 34, the first position of the anticodon of tRNAAsn, have been observed in eukaryotes during differentiation. We use Dictyostelium discoideum as a model system to elucidate the possible involvement of tRNAAsn in developmental processes. Vegetative amoebae were induced to undergo developmental transition by nutrient starvation. Since amino acid starvation alone is a specific stimulus initiating development and unacylated tRNAs might be involved in control mechanisms of protein synthesis, the level of aminoacylation of tRNAAsn isoacceptors has been investigated. As early as two minutes after the onset of development, the aminoacylation of tRNAAsn specifically was reduced to about 30%, whereas at the same time 10 other tRNA species were found to be charged normally, i.e. to 70-100%. One of the two major isoacceptors, tRNAAsn3, was completely deacylated, whereas the other one, tRNAAsn2, accounted for the residual aminoacylation. Analyses of the modified nucleosides of highly purified tRNAAsn2 and tRNAAsn3 are respectively, show that both isoacceptors are identical in their modification patterns except for the modification at the first position of the anticodon; tRNAAsn2 comprises queuine (Q), 7-[(4,5-cis-dihydroxy-2-cyclopenten-1-ylamino)methyl]-7-deazaguanine, whereas tRNAAsn3 contains guanine.
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PMID:Reduced aminoacylation of asparagine-transfer RNA early in the developmental cycle of Dictyostelium discoideum: modification pattern and possible significance of the uncharged isoacceptor tRNAAsn3. 691 78

Most bacteria have evolved a number of regulatory mechanisms which allow them to maintain a balanced and rather constant cellular composition in response to nutritional variations. In particular, when the availability of any aminoacyl-tRNA species becomes limiting (namely through amino acid starvation or inactivation of an aminoacyl-tRNA synthetase), several biochemically distinct physiological processes are significantly modified. This coordinate adjustment of cellular activity is termed the "stringent response". Under such conditions of aminoacyl-tRNA limitation, protein synthesis still proceeds, but various quantitative as well as qualitative changes in polypeptide metabolism can be observed. In this review, after a brief recall of the main characteristics of the stringent response, several aspects concerning protein synthesis in deprived bacteria have been presented. First, the rates of residual protein formation, peptide chain growth and protein degradation, and the molecular weight distribution of proteins newly synthesized have been analyzed. Then, the data relative to the biosynthetic regulation of non-ribosomal and ribosomal proteins have been summarized and compared to the results obtained from in vitro experiments using transcription-translation coupled systems. Finally, the problem of translational fidelity during deprivation has been discussed in connection with the metabolic behavior of polysomal structures which are still maintained in cells. The stringent dependence of cellular activity on aminoacyl-tRNA supply is known to be abolished by single-site mutations which confer to bacteria a phenotype referred to as "relaxed". These mutant strains provide an useful analytical tool in the scope of understanding the stringency phenomenon. Therefore, their proteosynthetic activity under aminoacyl-tRNA deprivation has also been studied here, in comparison to that of normal wild-type strains.
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PMID:Stringent control and protein synthesis in bacteria. 700 94

Production of active lysosomal enzymes may involve limited proteolysis of inactive high molecular weight precursors. Precursor processing potentially regulates lysosomal enzyme activity. To test whether rabbit cardiac cathepsin D is first synthesized as a precursor and whether prolonged fasting (a condition affecting both cathepsin D and total cardiac protein turnover) influences precursor processing, rates of cathepsin D synthesis and processing were compared in left ventricular slices of control and 3-d-fasted rabbits incubated in vitro with [(35)S]methionine. (35)S-labeled cathepsin D was isolated by butanol-Triton X-100 extraction, immunoprecipitation, and dodecyl sulfate-polyacrylamide gel electrophoresis. Total cardiac protein synthesis was measured by tracer incorporation and normalized for differences in precursor pool size by direct measurement of [(35)S]aminoacyl-tRNA-specific radioactivity. Relative cathepsin D synthetic rates were obtained by comparing (35)S incorporation into cathepsin D with (35)S incorporation into all cardiac proteins. Enzyme processing was assessed in pulse-chase experiments and assayed by autoradiography. The results indicate that (a) rabbit cardiac cathepsin D is synthesized as a precursor (53,000 mol wt) that is processed to a 48,000-mol wt form, (b) rates of both cathepsin D and total cardiac protein synthesis are similar in control and fasted rabbits, suggesting that decreased enzyme degradation rather than increased synthesis is responsible for the elevated levels of cardiac cathepsin D in starvation, and (c) cathepsin D processing in hearts of fasted animals is incomplete, with accumulation of the precursor during pulse-chase experiments of 6 h duration. Based upon these results, a three-stage model for the regulation of cathepsin D activity in rabbit heart is proposed.
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PMID:Regulation of cathepsin D metabolism in rabbit heart: evidence for a role for precursor processing in the control of enzyme activity. 707 56

A key attribute of the stringent response of bacteria is the rapid inhibition of ribosomal RNA synthesis mediated by unusual nucleotides in respnse to uncharged tRNA. The question as to whether mammalian cells show a stringent response analogous to that of bacteria was critically tested by the effective rapid amino acid starvation of both normal and transformed cells. Rapid starvation giving a high proportion of uncharged tRNA for leucine was produced within 7 minutes of expression of a nonleaky ts leucyl tRNA synthetase mutation in transformed CHO cells (tsH1) and in its normal growth control revertant (L-73). To control for the effect of temperature alone, ts revertants of tsH1 and L-73 were included in the study, and to control for effects due simply to the inhibition of protein synthesis, the translational elongation inhibitor cycloheximide was used. In addition, rapid starvation for histidine was effected by incubation of both the CHO cell lines and of freshly explanted normal Chinese hamster embryo fibroblasts in histidine-free medium containing high concentrations of histidinol. The rate of preribosomal RNA synthesis and the extent of its maturation to mature rRNA was measured using (3H-methyl) methionine as a donor of methyl groups during synthesis and methylation of pre-rRNA. There was no effect on pre-rRNA synthesis of the rapid generation of uncharged tRNA for 45 minutes for any of the cell types tested. A nonspecific inhibition of maturation of 18S rRNA and late (3 hour) inhibition of pre-rRNA synthesis was observed, but could be mimicked by the inhibition of protein synthesis to comparable levels with cycloheximide. Less severe amino acid starvation resulting in a more physiological inhibition of protein synthesis to 30% also had no specific effect on pre-rRNA synthesis and maturation. Intracellular nucleotide pools were also examined for the appearance of unusual nucleotides such as guanosine tetraphosphate or pentaphosphate and for changes in the levels of normal nucleotides after severe amino acid starvation. No such changes could be detected. We conclude that although mammalian cells may have some biochemical reactions which respond to uncharged tRNA, they do not possess a macromolecular control system analogous to the stringent response of bacteria.
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PMID:Mammalian cells do not have a stringent response. 746 30

The thrS gene in Bacillus subtilis is specifically induced by starvation for threonine and is, in addition, autorepressed by the overproduction of its own gene product, the threonyl-tRNA synthetase. Both methods of regulation employ an antitermination mechanism at a factor-independent transcription terminator that occurs just upstream of the start codon. The effector of the induction mechanism is thought to be the uncharged tRNA(Thr), which has been proposed to base pair in two places with the leader mRNA to induce antitermination. Here we show that the autoregulation by synthetase overproduction is likely to utilize a mechanism similar to that characterized for induction by amino acid starvation, that is by altering the levels of tRNA charging in the cell. We also demonstrate that the base pairing interaction at the two proposed contact points between the tRNA and the leader are necessary but not always sufficient for either form of regulation. Finally, we present evidence that the thrS gene is expressed in direct proportion to the growth rate. This method of regulation is also at the level of antitermination but is independent of the interaction of the tRNA with the leader region.
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PMID:Aminoacyl-tRNA synthetase gene regulation in Bacillus subtilis: induction, repression and growth-rate regulation. 747 65

We show that the RNA chain growth rate on lacZ is reduced by an elevated ppGpp level even in the absence of starvation. Under these conditions the polypeptide chain elongation rate is affected little, if at all. These results lead us to re-examine the role of ppGpp in the reduction of protein synthesis and translational fidelity during amino acid starvation. We find that ppGpp has little or no direct effect on translation rate or fidelity. Rather, the effects of ppGpp on translation are indirectly caused by the fact that ppGpp inhibits mRNA synthesis, making mRNA limiting for translation during amino acid starvation. The reduced level of mRNA thereby reduces the severity of the aminoacyl-tRNA limitation and, in turn, decreases mistranslation. Mistranslation in the starved relA strain therefore results from an increased severity of aminoacyl-tRNA limitation due to the failure of this strain to reduce mRNA levels by increasing the level of ppGpp. Finally, the initial rise of the ppGpp level in the starved stringent strain, followed by a characteristic reduction to a steady poststarved level, can now be explained by the initially high, and then decreasing number of "hungry" codons adjusted through the mRNA pool.
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PMID:High concentrations of ppGpp decrease the RNA chain growth rate. Implications for protein synthesis and translational fidelity during amino acid starvation in Escherichia coli. 750 88

When stationary phase E. coli WU3610, carrying an ochre mutation in the tyrA gene, were incubated on plates lacking tyrosine, tyrosine-independent (Tyr+) mutants appeared from day 7 onwards in a time-dependent manner. These starvation-associated mutants did not contain either identifiable tRNA suppressors or reversions at the ochre site and are thus quite distinct from the mutants commonly found to arise during active growth. When an appropriate fluctuation assay protocol was employed slow growing Tyr+ mutants were also found to arise in growing cells, and their distribution was more characteristic of a replication-dependent than a time-dependent process. The rate of appearance of starvation-associated mutants at 37 degrees C was somewhat less than at 27 degrees C and this was attributed to a reduction in viability at the higher temperature. There was no evidence for the accumulation on the plates of mutations in other genes. Tyr+ mutants were, however, shown to arise during incubation of stationary phase cells under conditions where there was no selection for tyrosine independence, provided outgrowth was subsequently permitted on plates lacking tyrosine. This distinguishes the present system from those systems exhibiting genuine "directed" or "adaptive" mutation, should they exist. To explain the specificity which occurs, it is proposed that the appearance of stationary mutants in ochre strains reflects the time-dependent accumulation in the transcribed strand of a DNA lesion that has a high probability of miscoding during transcription and replication. A mutant RNA transcript permits protein synthesis which in turn triggers DNA replication. The mutation is then fixed in the DNA as a permanent heritable change. The apparent "directedness" of the process is, on this model, determined solely by the particular miscoding DNA lesion occurring in a transcribed strand at a site where a change in phenotype permits DNA replication to occur.
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PMID:Starvation-associated mutation in Escherichia coli: a spontaneous lesion hypothesis for "directed" mutation. 751 91

Using fusions between the Escherichia coli genes argI and lacZ, it has been demonstrated that ribosomal frameshifting occurs at a frequency of between 3% and 16% within the argI mRNA, soon after the initiation codon. The frameshift involves a phenylalanyl-tRNA shifting into the +1 frame at the sequence UUU-U/C. The shift does not occur if the in-frame phenylalanine codon UUU is replaced by UUC. The level of frameshifting is higher in dense cultures and is not dependent on phenylalanine starvation. In the wild-type argI gene this frameshifting event would be an error, leading to a truncated, non-functional protein. Therefore, it is unlike the numerous examples of required frameshifting events that have been described in other genes.
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PMID:A ribosomal frameshifting error during translation of the argI mRNA of Escherichia coli. 751 62

The concentration of guanosine 3',5'-bispyrophosphate (ppGpp) increases in bacteria in response to amino acid or carbon/energy source starvation. An Escherichia coli K12 delta relA delta spoT mutant lacking the ability to synthesize ppGpp lost viability at an increased rate during both glucose and seryl-tRNA starvation. Also, the deleterious effect of chloramphenicol on starved wild-type cells could be overcome by inducing expression of RelA from a plasmid carrying the relA gene transcribed from a tac promoter, prior to starvation and chloramphenicol treatment. As demonstrated by two dimensional gel electrophoresis, this induction of the RelA protein resulted in global alterations in gene expression including increased synthesis of some rpoS-dependent proteins. The delta relA delta spoT mutant maintained high expression of several ribosomal proteins during starvation and appeared to exhibit significantly decreased translational fidelity, as demonstrated by an unusual heterogeneity in the isoelectric point of several proteins and the failure to express higher molecular weight proteins during starvation. Moreover, both rpoS-dependent and independent genes failed to exhibit increased expression in the mutant. It is suggested that the deleterious effects on the cells of the relA, spoT deletions are not due solely to the inability of these cells to induce the sigma factor sigma s, but also to deficiencies in translational fidelity and failure to exert classical stringent regulation.
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PMID:Role of guanosine tetraphosphate in gene expression and the survival of glucose or seryl-tRNA starved cells of Escherichia coli K12. 752 54

1. Incubation of Escherichia coli with 0.7 mM doxorubicin in MBS-glucose medium resulted in complete growth inhibition, an inhibition that was blocked by placing specific amino acids (AA) in the medium. 2. The mechanism of protection by AA was similar to that reported previously for cells poisoned by hyperoxia and by paraquat, e.g. of 20 common AA, ten percent, ten do not and the branched-chair AA are among those required for inhibition. 3. Unlike hyperoxia and paraquot stringency which caused elevation of intracellular concentrations of guanosine tetraphosphate (ppGpp), doxorubicin inhibition did not elevate ppGpp. 4. Concentrations of ppGpp were increased by isoleucine starvation as expected, and the subsequent addition of doxorubicin did not abolish that increase; however, pretreatment with doxorubicin prevented the induction of stringency by isoleucine starvation. 5. This suggests that doxorubicin directly inhibits ppGpp synthesis or protein biosynthesis to leave tRNA loaded as is the case with chloramphenicol.
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PMID:Protection by selective amino acid solutions against doxorubicin induced growth inhibition of Escherichia coli. 755 72


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