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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central role of the ubiquitin-proteasome system in the loss of skeletal muscle protein in many wasting conditions has been well established. However, it is unclear what factors are responsible for the suppression of this system during periods of protein gain. Thus, the aim of these studies was to examine the short-term effects of insulin release and nutrients on skeletal muscle protein turnover in young rats starved for 48 h, and then infused intravenously with amino acids (AA), or fed an oral diet. Forty-eight hours of starvation (i.e. prolonged starvation in young rats) decreased muscle protein synthesis and increased proteasome-dependent proteolysis. Four-hour AA infusion and 4 h of refeeding increased plasma insulin release and AA concentrations, and stimulated muscle protein synthesis, but had no effect on either total or proteasome-dependent proteolysis, despite decreased plasma corticosterone concentrations. Both muscle proteasome-dependent proteolysis and the rate of ubiquitination of muscle proteins were not suppressed until 10 h of refeeding. The temporal response of these two measurements correlated with the normalised expression of the 14-kDa E2 (a critical enzyme in substrate ubiquitination in muscle) and the expression of the MSS1 subunit of the 19S regulatory complex of the 26S proteasome. In contrast, the starvation-induced increase in mRNA levels for 20S proteasome subunits was normalised by refeeding within 24 h in muscle, and 6 h in jejunum, respectively. In conclusion, unlike protein synthesis, skeletal muscle proteasome-dependent proteolysis is not acutely responsive in vivo to insulin, AA, and/or nutrient intake in refed starved rats. This suggests that distinct and perhaps independent mechanisms are responsible for the nutrient-dependent regulation of protein synthesis and ubiquitin-proteasome-dependent proteolysis following a prolonged period of catabolism. Furthermore, factors other than the expression of ubiquitin-proteasome pathway components appear to be responsible for the suppression of skeletal muscle proteasome-dependent proteolysis by nutrition.
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PMID:Ubiquitin-proteasome-dependent muscle proteolysis responds slowly to insulin release and refeeding in starved rats. 1256 2

When mammalian cells are exposed to cisplatin or ultraviolet irradiation, the RNA polymerase II (RNAP II) large subunit becomes ubiquitinated and is subsequently degraded via the proteasomal pathway. Using a DNA template immobilized on magnetic beads in an in vitro transcription reaction, we showed that a pause of the elongating RNAP II complex caused by nucleotide starvation induced the ubiquitination of the stalled RNAP II. The ubiquitinated RNAP II dissociated from the ternary complex when transcription was allowed to resume. The dissociated (free) RNAP II remained ubiquitinated. The proteasome inhibitor MG132 increased the accumulation of ubiquitinated free RNAP II but did not affect the amount of ubiquitinated, template-bound RNAP II, indicating that the ubiquitinated RNAP II was displaced from the template and then degraded by the proteasomes. Our work shows that the elongation complex that was stalled at the template by nucleotide starvation is targeted by the ubiquitin-conjugating system and that ubiquitination facilitates displacement of the stalled RNAP II from the template. Our findings together with the findings by others that DNA damaging agents induced the ubiquitination in mammalian cells that are nucleotide excision repair competent, suggest that the RNAP II ubiquitination may have a role in the regulation of transcription-coupled DNA repair.
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PMID:RNA polymerase II stalled on a DNA template during transcription elongation is ubiquitinated and the ubiquitination facilitates displacement of the elongation complex. 1257 24

The contribution of the main proteolytic pathways to the degradation of long-lived proteins in human fibroblasts grown under different conditions was investigated. The effects of various commonly used pharmacological inhibitors of protein degradation were first analysed in detail. By choosing specific inhibitors of lysosomes and proteasomes, it was observed that together both pathways accounted for 80% or more of the degradation of cell proteins. With lysosomal inhibitors, it was found that serum withdrawal or amino-acid deprivation strongly stimulated macroautophagy but not other lysosomal pathways, whereas confluent conditions had no effect on macroautophagy and slightly activated other lysosomal pathways. Prolonged (24 h) serum starvation of confluent cultures strongly decreased the macroautophagic pathway, whereas the activity of other lysosomal pathways increased. These changes correlated with electron microscopic observations and morphometric measurements of lysosomes. With proteasomal inhibitors, it was found that, in exponentially growing cells in the absence of serum, activity of the ubiquitin-proteasome pathway increases, whereas under confluent conditions the contribution (in percentage) of proteasomes to degradation decreases, especially in cells deprived of amino acids. Interestingly, in confluent cells, the levels of two components of the 19 S regulatory complex and those of an interchangeable beta-subunit decreased. This was associated with a marked increase in the levels of components of PA28-immunoproteasomes. Thus confluent conditions affect proteasomes in a way that resembles treatment with interferon-gamma. Altogether, these results show that the activity of the various proteolytic pathways depends on the growth conditions of cells and will be useful for investigation of the specific signals that control their activity.
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PMID:Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions. 1284 50

During prolonged starvation, yeast cells enter a stationary phase (SP) during which the synthesis of many proteins is dramatically decreased. We show that a parallel decrease in proteasome-dependent proteolysis also occurs. The reduction in proteolysis is correlated with disassembly of 26S proteasome holoenzymes into their 20S core particle (CP) and 19S regulatory particle (RP) components. Proteasomes are reassembled, and proteolysis resumes prior to cell cycle reentry. Free 20S CPs are found in an autoinhibited state in which the N-terminal tails from neighboring alpha subunits are anchored by an intricate lattice of interactions blocking the channel that leads into the 20S CPs. By deleting channel gating residues of CP alpha subunits, we generated an "open channel" proteasome that exhibits faster rates of protein degradation both in vivo and in vitro, indicating that gating contributes to regulation of proteasome activity. This open channel mutant is delayed in outgrowth from SP and cannot survive following prolonged starvation. In summary, we have found that the ubiquitin-proteasome pathway can be subjected to global downregulation, that the proteasome is a target of this regulation, and that proteasome downregulation is linked to survival of SP cells. Maintaining high viability during SP is essential for evolutionary fitness, which may explain the extreme conservation of channel gating residues in eukaryotic proteasomes.
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PMID:Proteasome disassembly and downregulation is correlated with viability during stationary phase. 1284 14

Peripheral blood monocytes utilize free glutamine (Gln) in addition to glucose as an important energy substrate. Although this demand increases upon activation, monocytes are commonly confronted with decreased plasma Gln during critical illness and thus suffer from Gln-starvation. Here we investigate the influence of Gln-starvation on protein stability and its effects on the monocyte proteome. Gln-starvation caused a reduction of protein degradation which was accompanied by an accumulation of ubiquitin-protein conjugates and a reduction of intracellular ATP. Similar effects were observed under ATP-reducing conditions and in the presence of a proteasome inhibitor. Using two-dimensional gel electrophoresis we identified the IL-1beta precursor protein (pIL-1beta) as the, by far, most induced protein in endotoxin-treated monocytes. The degradation of the short-lived pIL-1beta was strongly reduced during Gln-starvation, while the degradation of the long-lived, constitutively expressed beta-actin was less affected. This indicates that although Gln-starvation reduces protein breakdown on the overall proteasome level, it leads to differential changes in the stability of specific proteins. This selective effect is likely to contribute to the immunocompromised state of monocytes commonly observed during critical illness.
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PMID:Glutamine starvation of monocytes inhibits the ubiquitin-proteasome proteolytic pathway. 1285 19

Using a synthetic lethality screen we found that the Sit4 phosphatase is functionally linked to the ubiquitin-proteasome system. Yeast cells harboring sit4 mutations and an impaired proteasome (due to pre1-1 pre4-1 mutations) exhibited defective growth on minimal medium. Nearly identical synthetic effects were found when sit4 mutations were combined with defects of the Rad6/Ubc2- and Cdc34/Ubc3-dependent ubiquitination pathways. Under synthetic lethal conditions, sit4 pre or sit4 ubc mutants formed strongly enlarged unbudded cells with a DNA content of 1N, indicating a defect in the maintenance of cell integrity during starvation-induced G(1) arrest. Sit4-related synthetic effects could be cured by high osmotic pressure or by the addition of certain amino acids to the growth medium. These results suggest a concerted function of the Sit4 phosphatase and the ubiquitin-proteasome system in osmoregulation and in the sensing of nutrients. Further analysis showed that Sit4 is not a target of proteasome-dependent protein degradation. We could also show that Sit4 does not contribute to regulation of proteasome activity. These data suggest that both Sit4 phosphatase and the proteasome act on a common target protein.
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PMID:Sit4 phosphatase is functionally linked to the ubiquitin-proteasome system. 1293 Jul 41

The Gcn4 protein, a member of the AP-1 family of transcription factors, is involved in the expression of more than 500 genes in the budding yeast Saccharomyces cerevisiae. A key role of Gcn4p is the increased expression of many amino acid biosynthesis genes in response to amino acid starvation. The accumulation of this transcription activator is mainly induced by efficient translation of the GCN4 ORF and by stabilisation of the Gcn4 protein. Under normal growth conditions, Gcn4p is a highly unstable protein, thereby resembling many eukaryotic transcription factors, including mammalian Jun and Myc proteins. Gcn4p is degraded by ubiquitin-dependent proteolysis mediated by the Skp1/cullin/F-box (SCF) ubiquitin ligase, which recognises specifically phosphorylated substrates. Two cyclin-dependent protein kinases, Pho85p and Srb10p, have crucial functions in regulating Gcn4p phosphorylation and degradation. The past few years have revealed many novel insights into these regulatory processes. Here, we summarise current knowledge about the factors and mechanisms regulating Gcn4p stability.
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PMID:Controlling transcription by destruction: the regulation of yeast Gcn4p stability. 1450 4

Circulating levels of glucocorticoids are increased in many traumatic and muscle-wasting conditions that include insulin-dependent diabetes, acidosis, infection, and starvation. On the basis of indirect findings, it appeared that these catabolic hormones are required to stimulate Ub (ubiquitin)-proteasome-dependent proteolysis in skeletal muscles in such conditions. The present studies were performed to provide conclusive evidence for an activation of Ub-proteasome-dependent proteolysis after glucocorticoid treatment. In atrophying fast-twitch muscles from rats treated with dexamethasone for 6 days, compared with pair-fed controls, we found (i) increased MG132-inhibitable proteasome-dependent proteolysis, (ii) an enhanced rate of substrate ubiquitination, (iii) increased chymotrypsin-like proteasomal activity of the proteasome, and (iv) a co-ordinate increase in the mRNA expression of several ATPase (S4, S6, S7 and S8) and non-ATPase (S1, S5a and S14) subunits of the 19 S regulatory complex, which regulates the peptidase and the proteolytic activities of the 26 S proteasome. These studies provide conclusive evidence that glucocorticoids activate Ub-proteasome-dependent proteolysis and the first in vivo evidence for a hormonal regulation of the expression of subunits of the 19 S complex. The results suggest that adaptations in gene expression of regulatory subunits of the 19 S complex by glucocorticoids are crucial in the regulation of the 26 S muscle proteasome.
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PMID:Glucocorticoids regulate mRNA levels for subunits of the 19 S regulatory complex of the 26 S proteasome in fast-twitch skeletal muscles. 1463 57

The cell wall-associated glyceraldehyde-3-phosphate dehydrogenase (cwGAPDH) activity in Saccharomyces cerevisiae increases (two- to 10-fold, depending on the strain) in response to starvation and temperature upshift. Assays using transformants carrying pTDH, a yeast centromer derivative plasmid containing the Candida albicans TDH3 gene (encoding GAPDH) fused in frame with the yeast SUC2-coding region for internal invertase, showed that starvation and/or temperature upshift result in a similar increase in both cwGAPDH and cell wall-associated invertase activities. In addition, this incorporation of GAPDH protein into the cell wall in response to stress does not require (i) de novo protein synthesis, indicating that preexisting cytosolic enzyme is incorporated into the cell wall, (ii) nor the participation of the ubiquitin yeast stress response system, as no differences were observed between wild-type and polyubiquitin-depleted (Deltaubi4) strains.
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PMID:Starvation and temperature upshift cause an increase in the enzymatically active cell wall-associated glyceraldehyde-3-phosphate dehydrogenase protein in yeast. 1465 34

Delivery of proteins and organelles to the vacuole by autophagy and the cytoplasm to vacuole targeting (Cvt) pathway involves novel rearrangements of membrane resulting in the formation of vesicles that fuse with the vacuole. The mechanism of vesicle formation and the origin of the membrane are complex issues still to be resolved. Atg18 and Atg21 are proteins essential to vesicle formation and together with Ygr223c form a novel family of phosphoinositide binding proteins that are associated with the vacuole and perivacuolar structures. Their localization requires the activity of Vps34, suggesting that phosphatidylinositol(3)phosphate may be essential for their function. The activity of Atg18 is vital for all forms of autophagy, whereas Atg21 is required for the Cvt pathway but not for nitrogen starvation-induced autophagy. The loss of Atg21 results in the absence of Atg8 from the pre-autophagosomal structure (PAS), which may be ascribed to a reduced rate of conjugation of Atg8 to phosphatidylethanolamine. A similar defect in localization of a second ubiquitin-like conjugate, Atg12-Atg5, suggests that Atg21 may be involved in the recruitment of membrane to the PAS.
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PMID:Atg21 is a phosphoinositide binding protein required for efficient lipidation and localization of Atg8 during uptake of aminopeptidase I by selective autophagy. 1515 9


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