Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We show that phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2) by the protein kinase GCN2 mediates translational control of the yeast transcriptional activator GCN4. In vitro, GCN2 specifically phosphorylates the alpha subunit of rabbit or yeast eIF-2. In vivo, phosphorylation of eIF-2 alpha increases in response to amino acid starvation, which is dependent on GCN2. Substitution of Ser-51 with alanine eliminates phosphorylation of eIF-2 alpha by GCN2 in vivo and in vitro and abolishes increased expression of GCN4 and amino acid biosynthetic genes under its control in amino acid-starved cells. The Asp-51 substitution mimics the phosphorylated state and derepresses GCN4 in the absence of GCN2. Thus, an established mechanism for regulating total protein synthesis in mammalian cells mediates gene-specific translational control in yeast.
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PMID:Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. 173 68

We have isolated a snf1/ccr1 mutant of Saccharomyces cerevisiae which loses viability upon starvation and fails to accumulate glycogen in response to abrupt depletion of phosphate or glucose. A snf1 null mutant is sensitive to heat stress and starvation and fails to accumulate glycogen during growth in rich medium. The phenotypes of the snf1 mutants are those commonly associated with an overactivation of the adenylate cyclase pathway. Mutations in adenylate cyclase or RAS2 which decrease the level of cAMP in the cell moderate the snf1 phenotype. In contrast, a mutation in RAS2 (RAS2val19) which increases the level of cAMP or a mutation in the regulatory subunit (BCY1) of cAMP-dependent protein kinase which results in unregulated cAMP-dependent protein kinase activity accentuates the snf1 phenotype. However, the action of SNF1 in the stress response appears at least partly independent of cAMP-dependent protein kinase because a snf1 phenotype is observed in a strain that lacks all three of the genes that encode the catalytic subunits of cAMP-dependent protein kinase. SNF1 therefore acts at least in part through a cAMP-independent pathway.
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PMID:Deletion of SNF1 affects the nutrient response of yeast and resembles mutations which activate the adenylate cyclase pathway. 175 15

The p107wee1 protein kinase plays a central role in regulating the cell cycle of fission yeast. It mediates transmission of signal(s) related to the nutritional status of the cell to the p34cdc2 protein kinase, which is an active component of the MPF complex driving cells into mitosis. p107wee1 is itself subject to control by the products of other genes such as nim1+/cdr1+, win1+, and perhaps wis1+ and other wis+ genes. At present, the relationships between these genes and their possible roles in the mitotic control are unclear and must await further analysis (Fig. 5). It is likely that some of the gene products are concerned with the sensing and/or transmission of nutritional signals. p107wee1 negatively regulates the activity of p34cdc2, probably by direct tyrosine phosphorylation, and also appears to regulate the activities of the cdc1+ and cdc27+ gene products. The effects of nitrogen starvation and of wee1 mutations on conditional lethal mutations at the cdc1, cdc2, and cdc27 loci, taken together, support the largely speculative model shown in Figure 5. During the normal cycle, the balance between phosphorylated and dephosphorylated p34cdc2 changes such that at the appropriate time, p34cdc2 is activated and the cell enters mitosis. We suggest that the cdc1+ and cdc27+ products may be regulated in a similar way. Such a mechanism would ensure coordinated activation of these and perhaps other proteins required for the G2/M transition. There are, of course, many uncertainties, and these must await elucidation by biochemical and genetic analysis.
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PMID:New elements in the mitotic control of the fission yeast Schizosaccharomyces pombe. 181 10

Transcription of the CTT1 (catalase T) gene of Saccharomyces cerevisiae is controlled by oxygen via heme, by nutrients via cAMP and by heat shock. Nitrogen limitation triggers a rapid, cycloheximide-insensitive derepression of the gene. Residual derepression in a cAMP-nonresponsive mutant with attenuated protein kinase activity (bcy1 tpk1w tpk2 tpk3) demonstrates the existence of an alternative, cAMP-independent nutrient signaling mechanism. Deletion analysis using CTT1-lacZ fusion genes revealed the contribution of multiple control elements to derepression, not all of which respond to the cAMP signal. A positive promoter element responding to negative control by cAMP was inactivated by deletion of a DNA region between base pairs -340 and -364. Upstream fragments including this element confer negative cAMP control to a LEU2-lacZ fusion gene. Northern analysis of CTT1 expression in the presence or absence of heme, in RAS2+ (high cAMP) and ras2 mutant (low cAMP) strains and in cells grown at low temperature (23 degrees C) and in heat-shocked cells (37 degrees C) shows that CTT1 is only induced to an appreciable extent when at least two of the three factors contributing to its expression (oxidative stress signaled by heme, nutrient starvation (low cAMP) and heat stress) activate the CTT1 promoter.
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PMID:Negative regulation of transcription of the Saccharomyces cerevisiae catalase T (CTT1) gene by cAMP is mediated by a positive control element. 184 76

Two Dictyostelium discoideum protein kinase(PK)-encoding cDNAs (Dd PK1 and Dd PK2) have been isolated by hybridization with an oligodeoxyribonucleotide derived from a highly conserved region of eukaryotic PKs. The two nucleotide (nt) sequences encode new putative serine/threonine-specific PKs. Dd PK1 is a partial cDNA covering the entire catalytic domain. The derived amino acid (aa) sequence is about 30% identical to both cAMP-dependent protein kinase (cAPK) and protein kinase C. The Dd PK2 sequence was extended through the isolation of a genomic fragment encoding a complete putative protein. A single intron is present, as deduced from sequence comparison with the cDNA. The catalytic domain appears more closely related to the catalytic subunit of cAPK (54% sequence identity). However, our nt sequence potentially codes for a much larger protein (648 vs. about 350 aa for most cAPKs) with a N-terminal half containing long homopolymers of threonines, glutamines and asparagines. Similar repeats occur at the C terminus of Dd PK1, Dd PK1 is expressed in vegetatively growing cells and during development. Dd PK1 RNA decreases after 6 h of starvation to re-accumulate once the cells have aggregated. Dd PK2 transcripts, present at a low amount in growing cells, rise upon starvation. A switch to a shorter form of transcripts occurs between 3 and 6 h into development.
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PMID:Isolation of two genes encoding putative protein kinases regulated during Dictyostelium discoideum development. 186 10

The role of cyclic AMP in acute regulation of the metabolism of mammary tissue in the lactating rat was examined by measuring the activity ratio of cyclic AMP-dependent protein kinase (A-kinase) and by examining the properties of this enzyme in its two major isoenzymic forms. Isoenzyme II is the major form in soluble extracts of rat mammary tissue. A-kinase activity ratio in such extracts is unaffected by starvation of the lactating rat. Treatment of the intact rat with isoprenaline, or addition of isoprenaline to incubations in vitro of mammary acini, resulted in a major increase in the activity ratio of A-kinase. These treatments equally affected isoenzymes I and II. The treatment in vitro lead to a rapid depletion of A-kinase as subsequently measured in extracts of acini. The degree of activation of the enzymes acetyl-CoA carboxylase and glycogen phosphorylase in extracts of mammary tissue and of acini was assessed as a function of these treatments. The increased activation of A-kinase induced by isoprenaline was unaccompanied by significant changes in the activity of acetyl-CoA carboxylase in acini, although we previously showed that this agent activates acetyl-CoA carboxylase in intact mammary tissue. Contrastingly, isoprenaline-induced enhancement of A-kinase activity was accompanied by an increase in the activity ratio of phosphorylase in acini. These results indicate that: (a) a normal response of expressed A-kinase activity to cyclic AMP operates in mammary acini and mammary tissue from lactating rats; (b) rapid modulation of the total amount of soluble A-kinase is mediated in mammary epithelial cells by cyclic AMP; (c) phosphorylase, an ultimate target of the protein phosphorylation cascade initiated by A-kinase, is activated in acini under conditions where A-kinase activity is enhanced; and (d) mechanisms other than that of the A-kinase phosphorylation/inhibition model for acetyl-CoA carboxylase regulation must operate in mammary tissue preparations and in vivo to account for the response of this enzyme to enhanced A-kinase activity.
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PMID:Cyclic AMP-dependent protein kinase in mammary tissue of the lactating rat. Activity ratio and responsiveness of the target enzymes acetyl-CoA carboxylase and glycogen phosphorylase to beta-adrenergic stimulation. 196 34

Mouse mammary epithelial cells were plated onto 24-well culture plates (50,000 per well), allowed to attach and serum starved for 24 h. Following serum starvation, DNA synthesis was induced by the addition of 10% fetal calf serum and determined by a 1-h pulse with [3H]thymidine from 17 to 18 h after serum addition. Addition of oligonucleotides antisense to the translation start region of cyclic AMP-dependent protein kinase (kinase A) mRNA inhibited thymidine incorporation into DNA (total or percentage of cells incorporating thymidine, as measured by autoradiography). This inhibition was apparent whether compared to controls with no oligonucleotide addition, sense oligonucleotides, or mismatch oligonucleotides. Enzymatic assays indicated that the antisense oligonucleotides lowered kinase A activity in cells. Time course studies indicated that the inhibition in DNA synthesis was not an artifact of the time at which DNA synthesis was estimated. Long-term (4 day) cultures indicated that effects on induction of DNA synthesis were reflected in long-term cell proliferation.
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PMID:Oligonucleotides antisense to catalytic subunit of cyclic AMP-dependent protein kinase inhibit mouse mammary epithelial cell DNA synthesis. 198 19

Ten spontaneous and four in vitro constructed mutations in the gene encoding the regulatory subunit of cAMP-dependent protein kinase of Saccharomyces cerevisiae display very different phenotypes. The DNA nucleotide sequence of each spontaneous mutation was determined. Mutations were found in both the cAMP-binding domains and proximal to the cAMP-dependent protein kinase phosphorylation site. The latter mutations exhibited dominant traits when gene dosage was increased. The variation of phenotypes of sra1 mutations was examined. Many aspects of growth are affected, including growth on nonfermentable carbon sources, accumulation of glycogen, ability to sporulate, and ability to survive starvation. The null mutations affect all these traits. None of the spontaneous mutations confer the null phenotype. Instead, these mutations can be placed into groups of increasing severity based on the number of traits affected. These traits reflect the functions of the cAMP-dependent protein kinase substrates and ranking of sra1 phenotypes probably reflects a progressive defect in one or more aspects of the regulatory subunit function.
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PMID:Yeast cAMP-dependent protein kinase regulatory subunit mutations display a variety of phenotypes. 216 21

Fission yeast cell division is initiated by the cdc2/cdc13-cyclin protein kinase which in its catalytically active state comprises the mitotic inducer. During interphase the cdc2/cyclin complex is assembled in an inactive state that requires cdc25+ gene function for M-phase activation. The cdc25+ product, a 76 kd phosphoprotein, is shown to oscillate in abundance during the cell cycle, reaching a peak at G2/M, and to be sensitive to nitrogen starvation. The level of cdc25 is subject to feedback regulation involving both cdc25 and cdc2.
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PMID:Fission yeast cdc25 is a cell-cycle regulated protein. 217 10

GCN4 is a transcriptional activator of amino acid-biosynthetic genes in the yeast Saccharomyces cerevisiae. GCN2, a translational activator of GCN4 expression, contains a domain homologous to the catalytic subunit of eucaryotic protein kinases. Substitution of a highly conserved lysine residue in the kinase domain abolished GCN2 regulatory function in vivo and its ability to autophosphorylate in vitro, indicating that GCN2 acts as a protein kinase in stimulating GCN4 expression. Elevated GCN2 gene dosage led to derepression of GCN4 under nonstarvation conditions; however, we found that GCN2 mRNA and protein levels did not increase in wild-type cells in response to amino acid starvation. Therefore, it appears that GCN2 protein kinase function is stimulated posttranslationally in amino acid-starved cells. Three dominant-constitutive GCN2 point mutations were isolated that led to derepressed GCN4 expression under nonstarvation conditions. Two of the GCN2(Con) mutations mapped in the kinase domain itself. The third mapped just downstream from a carboxyl-terminal segment homologous to histidyl-tRNA synthetase (HisRS), which we suggested might function to detect uncharged tRNA in amino acid-starved cells and activate the adjacent protein kinase moiety. Deletions and substitutions in the HisRS-related sequences and in the carboxyl-terminal segment in which one of the GCN2(Con) mutation mapped abolished GCN2 positive regulatory function in vivo without lowering autophosphorylation activity in vitro. These results suggest that sequences flanking the GCN2 protein kinase moiety are positive-acting domains required to increase recognition of physiological substrates or lower the requirement for uncharged tRNA to activate kinase activity under conditions of amino acid starvation.
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PMID:Identification of positive-acting domains in GCN2 protein kinase required for translational activation of GCN4 expression. 218


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