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)

Protein synthesis is regulated in response to environmental stimuli by covalent modification, primarily phosphorylation, of components of the translational machinery. Phosphorylation of the alpha subunit of eIF-2 is one of the best-characterized mechanisms for down-regulating protein synthesis in higher eukaryotes in response to various stress conditions. Three distinct protein kinases regulate protein synthesis in eukaryotic cells by phosphorylating the alpha subunit of eIF-2 at serine-51. There are two mammalian eIF-2alpha kinases: the double-stranded RNA-dependent kinase (PKR) and heme-regulated inhibitor kinase (HRI), and the yeast GCN2. The regulatory mechanisms and the molecular sizes of these eIF-2alpha kinases are different. The expression of PKR is induced by interferon, and the kinase activity is stimulated by low concentrations of double-stranded RNA. HRI is activated under heme-deficient conditions. Yeast GCN2 is activated by amino acid starvation. The phosphorylation of eIF-2alpha results in the shutdown of protein synthesis. Nevertheless, the eIF-2alpha kinases can regulate both global as well as specific mRNA translation. Inhibition of protein synthesis correlates with eIF-2alpha phosphorylation in response to a wide variety of different stimuli, including heat shock, serum deprivation, glucose starvation, amino acid starvation, exposure to heavy metal ions, and viral infection. Finally, recent studies suggest a role for eIF-2alpha phosphorylation in the control of cell growth and differentiation.
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PMID:The eIF-2alpha kinases and the control of protein synthesis. 890 8

KFR1, a mitogen-activated protein (MAP) kinase identified in the African trypanosome, Trypanosoma brucei, is a serine protein kinase capable of phosphorylating the serine residues in histone H-1, myelin basic protein, and beta-casein. It phosphorylates four proteins with estimated molecular masses of 22, 34, 46, and 90 kDa from the T. brucei bloodstream-form lysate in vitro. KFR1 bears significant sequence similarity to the yeast MAP kinases KSS1 and FUS3 but cannot functionally complement the kss1/fus3 yeast mutant. It is encoded by a single-copy gene in the diploid T. brucei, and only one of the two alleles can be successfully disrupted, suggesting an essential function of KFR1 in T. brucei. KFR1 activity is present at a much enhanced level in the bloodstream form of T. brucei when compared with that in the insect (procyclic) form. This enhanced activity can be eliminated in vitro by the treatment with protein phosphatase HVH2 known to act specifically on MAP kinases. It can also be decreased in the bloodstream form of T. brucei by serum starvation but induced specifically by interferon-gamma. The production of interferon-gamma in the mammalian host is known to be triggered by T. brucei infection, and this cytokine, as has been reported, promotes the proliferation of T. brucei in the mammalian blood. Since none of these phenomena can be observed in the procyclic form of T. brucei, activation of KFR1 is most likely involved in mediating the interferon-gamma-induced proliferation of T. brucei in the mammalian host.
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PMID:Interferon-gamma activation of a mitogen-activated protein kinase, KFR1, in the bloodstream form of Trypanosoma brucei. 909 33

As a major component of mammalian cell plasma membranes, cholesterol is essential for cell growth. Accordingly, the restriction of cholesterol provision has been shown to result in cell proliferation inhibition. We explored the potential regulatory role of cholesterol on cell cycle progression. MOLT-4 and HL-60 cell lines were cultured in a cholesterol-deficient medium and simultaneously exposed to SKF 104976, which is a specific inhibitor of lanosterol 14-alpha demethylase. Through HPLC analyses with on-line radioactivity detection, we found that SKF 104976 efficiently blocked the [(14)C]-acetate incorporation into cholesterol, resulting in an accumulation of lanosterol and dihydrolanosterol, without affecting the synthesis of mevalonic acid. The inhibitor also produced a rapid and intense inhibition of cell proliferation (IC(50) = 0.1 microM), as assessed by both [(3)H]-thymidine incorporation into DNA and cell counting. Flow cytometry and morphological examination showed that treatment with SKF 104976 for 48 h or longer resulted in the accumulation of cells specifically at G2 phase, whereas both the G1 traversal and the transition through S were unaffected. The G2 arrest was accompanied by an increase in the hyperphosphorylated form of p34(cdc2) and a reduction of its activity, as determined by assaying the H1 histone phosphorylating activity of p34(cdc2) immunoprecipitates. The persistent deficiency of cholesterol induced apoptosis. However, supplementing the medium with cholesterol, either in the form of LDL or free cholesterol dissolved in ethanol, completely abolished these effects, whereas mevalonate was ineffective. Caffeine, which abrogates the G2 checkpoint by preventing p34(cdc2) phosphorylation, reduced the accumulation in G2 when added to cultures containing cells on transit to G2, but was ineffective in cells arrested at G2 by sustained cholesterol starvation. Cells arrested in G2, however, were still viable and responded to cholesterol provision by activating p34(cdc2) and resuming the cell cycle. We conclude that in both lymphoblastoid and promyelocytic cells, cholesterol availability governs the G2 traversal, probably by affecting p34(cdc2) activity.
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PMID:Cholesterol starvation decreases p34(cdc2) kinase activity and arrests the cell cycle at G2. 1042 60

In eukaryotic cells, protein synthesis is regulated in response to various environmental stresses by phosphorylating the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha). Three different eIF2alpha kinases have been identified in mammalian cells, the heme-regulated inhibitor (HRI), the interferon-inducible RNA-dependent kinase (PKR) and the endoplasmic reticulum-resident kinase (PERK). A fourth eIF2alpha kinase, termed GCN2, was previously characterized from Saccharomyces cerevisiae, Drosophila melanogaster and Neurospora crassa. Here we describe the cloning of a mouse GCN2 cDNA (MGCN2), which represents the first mammalian GCN2 homolog. MGCN2 has a conserved motif, N-terminal to the kinase subdomain V, and a large insert of 139 amino acids located between subdomains IV and V that are characteristic of the known eIF2alpha kinases. Furthermore, MGCN2 contains a class II aminoacyl-tRNA synthetase domain and a degenerate kinase segment, downstream and upstream of the eIF2alpha kinase domain, respectively, and both are singular features of GCN2 protein kinases. MGCN2 mRNA is expressed as a single message of approximately 5.5 kb in a wide range of different tissues, with the highest levels in the liver and the brain. Specific polyclonal anti-(MGCN2) immunoprecipitated an eIF2alpha kinase activity and recognized a 190 kDa phosphoprotein in Western blots from either mouse liver or MGCN2-transfected 293 cell extracts. Interestingly, serum starvation increased eIF2alpha phosphorylation in MGCN2-transfected human 293T cells. This finding provides evidence that GCN2 is the unique eIF2alpha kinase present in all eukaryotes from yeast to mammals and underscores the role of MGCN2 kinase in translational control and its potential physiological significance.
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PMID:Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. 1050 7

Protein kinase GCN2 regulates translation in amino acid-starved cells by phosphorylating elF2. GCN2 contains a regulatory domain related to histidyl-tRNA synthetase (HisRS) postulated to bind multiple deacylated tRNAs as a general sensor of starvation. In accordance with this model, GCN2 bound several deacylated tRNAs with similar affinities, and aminoacylation of tRNAphe weakened its interaction with GCN2. Unexpectedly, the C-terminal ribosome binding segment of GCN2 (C-term) was required in addition to the HisRS domain for strong tRNA binding. A combined HisRS+ C-term segment bound to the isolated protein kinase (PK) domain in vitro, and tRNA impeded this interaction. An activating mutation (GCN2c-E803V) that weakens PK-C-term association greatly enhanced tRNA binding by GCN2. These results provide strong evidence that tRNA stimulates the GCN2 kinase moiety by preventing an inhibitory interaction with the bipartite tRNA binding domain.
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PMID:Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. 1098 75

Immunodetection of protein carbonyl groups demonstrates that growth arrest elicited by carbon or nitrogen starvation causes an increased oxidation of proteins in Saccharomyces cerevisiae. Mutant analysis suggests that the response regulator Pos9p is involved in mitigating self-inflicted oxidative damages in G(0) cells, whereas Yap1p is primarily required in growing cells. The data also suggest that oxidation of target proteins is not a priori an effect of arrest of cell division or nutrient depletion and cannot be explained by the respiratory activity alone nor a high ratio of catabolic/anabolic activity in G(0) cells. Instead, we observed that starvation elicits a transition in the respiratory state (from phosphorylating to nonphosphorylating respiration) and that this transition is associated with a stepwise increase in protein oxidation. During carbon starvation, this transition and increase in oxidation occurs immediately as the carbon source is depleted, growth is arrested, and the respiratory rate falls drastically. In contrast, during nitrogen starvation and excess carbon the respiratory state transition and stepwise increase in protein oxidation are markedly delayed and occur long after the nitrogen source has been depleted and division and growth-arrested. Oxidation in G(0) cells could be enhanced by treating cells with low concentrations of antimycin A and attenuated with myxothiazol, indicating that protein oxidation is intimately linked to reactive oxygen species generated by semiquinones of the Q-cycle. Thus, the work presented suggests that the degree of coupling in the mitochondrial respiratory apparatus rather then the overall rate of respiration affects the degree of protein oxidation in nondividing yeast cells.
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PMID:Protein oxidation in G0 cells of Saccharomyces cerevisiae depends on the state rather than rate of respiration and is enhanced in pos9 but not yap1 mutants. 1143 67

Protein kinase GCN2 regulates translation initiation by phosphorylating eukaryotic initiation factor 2alpha (eIF2alpha), impeding general protein synthesis but specifically inducing translation of GCN4, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. GCN2 activity is stimulated in amino acid-deprived cells through binding of uncharged tRNA to a domain related to histidyl tRNA synthetase. We show that GCN2 is phosphorylated by another kinase on serine 577, located N-terminal to the kinase domain. Mutation of Ser-577 to alanine produced partial activation of GCN2 in nonstarved cells, increasing the level of phosphorylated eIF2alpha, derepressing GCN4 expression, and elevating the cellular levels of tryptophan and histidine. The Ala-577 mutation also increased the tRNA binding affinity of purified GCN2, which can account for the elevated kinase activity of GCN2-S577A in nonstarved cells where uncharged tRNA levels are low. Whereas Ser-577 remains phosphorylated in amino acid-starved cells, its dephosphorylation could mediate GCN2 activation in other stress or starvation conditions by lowering the threshold of uncharged tRNA required to activate the protein.
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PMID:Serine 577 is phosphorylated and negatively affects the tRNA binding and eIF2alpha kinase activities of GCN2. 1207 Jan 58

Mesangial cell proliferation is an early event in several progressive renal diseases. When mesangial cells in culture are rendered quiescent by serum starvation and subsequently stimulated to proliferate, induction of c-fos is an early indicator of entry into the cell cycle. Several heparin-sensitive signals transduce these events. We have examined the potential roles of CaMK and PKA. Selective stimulation of CaMK with Ca(2+) ionophores and of PKA with forskolin or dibutyryl cAMP both result in induction of c-fos mRNA. CaMK but not PKA signaling is suppressed by low concentrations of heparin. Cross talk between the pathways has been demonstrated in some cells, with evidence of CaMK phosphorylating cAMP response element binding protein (CREB) at an inhibitory site and PKA suppressing CaMK-dependent signaling. However, in the present study, both pathways phosphorylated CREB on Ser(133) and induced c-fos in an additive manner. Serum, ionomycin, and forskolin all caused a rapid decline in cyclin D1 levels, but only serum effected a subsequent increase, indicative of cell cycle progression. We conclude that, in human mesangial cells, CaMK and PKA can both contribute to cell cycle entry, and, although induction of c-fos by CaMK requires active PKA, neither pathway antagonizes or synergizes c-fos induction by the other.
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PMID:Ca(2+)/calmodulin-dependent and cAMP-dependent kinases in induction of c-fos in human mesangial cells. 1237 63

Yeast protein kinase GCN2 stimulates the translation of transcriptional activator GCN4 by phosphorylating eIF2alpha in response to amino acid starvation. Kinase activation requires binding of uncharged tRNA to a histidyl tRNA synthetase-related domain in GCN2. Phosphorylation of serine 577 (Ser 577) in GCN2 by another kinase in vivo inhibits GCN2 function in rich medium by reducing tRNA binding activity. We show that rapamycin stimulates eIF2alpha phosphorylation by GCN2, with attendant induction of GCN4 translation, while reducing Ser 577 phosphorylation in nonstarved cells. The alanine 577 (Ala 577) mutation in GCN2 (S577A) dampened the effects of rapamycin on eIF2alpha phosphorylation and GCN4 translation, suggesting that GCN2 activation by rapamycin involves Ser 577 dephosphorylation. Rapamycin regulates the phosphorylation of Ser 577 and eIF2alpha by inhibiting the TOR pathway. Rapamycin-induced dephosphorylation of Ser 577, eIF2alpha phosphorylation, and induction of GCN4 all involve TAP42, a regulator of type 2A-related protein phosphatases. Our results add a new dimension to the regulation of protein synthesis by TOR proteins and demonstrate cross-talk between two major pathways for nutrient control of gene expression in yeast.
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PMID:Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. 1265 28

Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.
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PMID:An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. 1266 46


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