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)

During a three-day fast, followed by four days of refeeding, the content of the multicatalytic proteinase as well as hydrolyzing activity towards Suc-Leu-Leu-Val-Tyr-7-amino-4-methylocoumarin (SLLVT-MCA) was measured in various rat tissues. When compared with normal rats, the MCP content, as determined by immunochemical techniques, was unchanged over the entire experimental period in the three tissues examined: gastrocnemius muscle, thymus and testis. By contrast, a differential response was observed in the three tissues with respect to specific and total SLLVT-MCA splitting activity: for thymus and testis, these values were again unchanged, whereas in gastrocnemius muscle, both specific and total enzyme activity fell by almost 70% on day three of fasting but returned to control values on day four of refeeding. This change in activity was not due to the accumulation or degradation of a specific proteinase inhibitor. Data demonstrate that, in association with the insulin-deficient state of starvation, the activity of the multicatalytic proteinase shows an adaptive behaviour which becomes manifest in some but not in other tissues.
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PMID:Tissue-specific changes of multicatalytic proteinase activity in the fasted rat. 184 9

Most of the increased protein degradation in muscle atrophy caused by starvation and denervation is due to activation of a non-lysosomal ATP-dependent proteolytic process. To determine whether expression of the ubiquitin-proteasome-dependent pathway is activated in atrophying muscles, we measured the levels of mRNA for ubiquitin (Ub) and proteasome subunits, and Ub content. After rats had been deprived of food for 1 or 2 days, the concentration of the two polyubiquitin (polyUb) transcripts increased 2-4-fold in the pale extensor digitorum longus muscle and 1-2.5-fold in the red soleus, whereas total muscle RNA and total mRNA content fell by 50%. After denervation of the soleus, there was a progressive 2-3-fold increase in polyUb mRNA for 1-3 days, whereas total RNA content fell. On starvation or denervation, Ub concentration in the muscles also rose by 60-90%. During starvation, polyUb mRNA levels also increased in heart, but not in liver, kidney, spleen, fat, brain or testes. Although the polyUb gene is a heat-shock gene that is induced in muscles under certain stressful conditions, the muscles of starving rats or after denervation did not express other heat-shock genes. On starvation or denervation, mRNA for several proteasome subunits (C-1, C-3, C-5, C-8 and C-9) also increased 2-4-fold in the atrophying muscles. When the food-deprived animals were re-fed, levels of Ub and proteasome mRNA in their muscles returned to control values within 1 day. In contrast, no change occurred in the levels of muscle mRNAs encoding cathepsin L, cathepsin D and calpain 1 on denervation or food deprivation. Thus polyUb and proteasome mRNAs increased in atrophying muscles in co-ordination with activation of the ATP-dependent proteolytic process.
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PMID:Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. 774 90

The rapid loss of skeletal-muscle protein during starvation and after denervation occurs primarily through increased rates of protein breakdown and activation of a non-lysosomal ATP-dependent proteolytic process. To investigate whether protein flux through the ubiquitin (Ub)-proteasome pathway is enhanced, as was suggested by related studies, we measured, using specific polyclonal antibodies, the levels of Ub-conjugated proteins in normal and atrophying muscles. The content of these critical intermediates had increased 50-250% after food deprivation in the extensor digitorum longus and soleus muscles 2 days after denervation. Like rates of proteolysis, the amount of Ub-protein conjugates and the fraction of Ub conjugated to proteins increased progressively during food deprivation and returned to normal within 1 day of refeeding. During starvation, muscles of adrenalectomized rats failed to increase protein breakdown, and they showed 50% lower levels of Ub-protein conjugates than those of starved control animals. The changes in the pools of Ub-conjugated proteins (the substrates for the 26S proteasome) thus coincided with and can account for the alterations in overall proteolysis. In this pathway, large multiubiquitinated proteins are preferentially degraded, and the Ub-protein conjugates that accumulated in atrophying muscles were of high molecular mass (> 100 kDa). When innervated and denervated gastrocnemius muscles were fractionated, a significant increase in ubiquitinated proteins was found in the myofibrillar fraction, the proteins of which are preferentially degraded on denervation, but not in the soluble fraction. Thus activation of this proteolytic pathway in atrophying muscles probably occurs initially by increasing Ub conjugation to cell proteins. The resulting accumulation of Ub-protein conjugates suggests that their degradation by the 26S proteasome complex subsequently becomes rate-limiting in these catabolic states.
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PMID:Increase in ubiquitin-protein conjugates concomitant with the increase in proteolysis in rat skeletal muscle during starvation and atrophy denervation. 774 91

Proteasomes are high-molecular-mass multisubunit complexes which are believed, either by themselves or as a part of the 26S proteinase complex, to play a central role in extralysosomal pathways of intracellular protein breakdown. We have addressed the degradation of proteasomes in rat liver, investigating the possible role of lysosomes. Affinity-purified antibodies against rat liver proteasomes were used for immunoblot analysis of isolated lysosomes. Although proteasomes are not found in lysosomes from normally fed rats, they were found to accumulate in lysosomes of rats treated with leupeptin (an inhibitor of lysosomal proteases) and could also be detected in lysosomes isolated from livers of starved (24 h) rats. Proteinase-K treatment of these fractions, as well as immunogold procedures, show that a proportion of the proteasomes are inside lysosomes. Comparison of the amount of proteasomes found in lysosomes by immunoblotting with their experimentally determined half life (8.3 days) is consistent with an important role of these organelles in the degradation of rat liver proteasomes. Nevertheless, these data do not exclude the possibility that some nonlysosomal degradation of proteasome components also occurs. Since proteasomes were localized in autophagic vacuoles, it is likely that they are taken up mainly by nonselective autophagy. However, using an in vitro system, it was found that, under conditions of starvation, proteasomes may also be taken up into lysosomes and degraded via the heat-shock cognate protein of 73 kDa (hsc73)-mediated transport.
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PMID:Degradation of proteasomes by lysosomes in rat liver. 786 40

1. Proteins in eukaryotic cells are continually degraded and replaced under precise control mechanisms. Although this continual proteolysis may seem wasteful, it serves several important functions: cells selectively degrade proteins with abnormal sequences or conformations, the accumulation of which could be harmful; the rapid degradation of regulatory peptides and enzymes is essential for the control of metabolic pathways and the cell cycle; and the breakdown of proteins in starvation provides amino acids for gluconeogenesis and energy metabolism. 2. Protein breakdown in eukaryotic cells occurs through distinct pathways: A) lysosomal (involves cathepsins B, H, L, etc.); B) Ca(2+)-dependent (involves Ca(2+)-dependent proteases calpains I and II); C) ATP-dependent, that require or not ubiquitin (comprises at least two large cytosolic proteases, UCDEN and proteasome), and D) ATP-independent (it is not known which proteases are involved in this degradative system). Despite recent dramatic progress, the relative contributions of these pathways to the accelerated proteolysis occurring in normal and pathological states is still largely unknown. 3. In order to identify the cellular mechanisms of skeletal muscle atrophy during fasting and diabetes mellitus, we have studied protein turnover in soleus and EDL muscles from control and fasted (for 24 h) or diabetic rats (1, 3, 5 and 10 days after streptozotocin injection). 4. The increase in muscle proteolysis during fasting seems to be attributable to an enhancement of the energy-requiring process. An increase in the ATP-dependent proteolytic pathway was evident 1 day after food restriction and probably accounted for all of the increased proteolysis demonstrated in the EDL muscles. In parallel with the alterations in the ATP-dependent process, an increase in the ubiquitin-mRNA and proteasome subunit-mRNA was detected. 5. In the acute phase of diabetes (1-3 days) there was an activation of Ca(2+)-dependent (soleus and EDL) and ATP-dependent (EDL) pathways. However, after 5 and 10 days of diabetes the activity of these two pathways fell to values even below control ones. No changes in the lysosomal proteolytic system were observed during diabetes. 6. Although appreciable progress has been made in this research, a large number of important questions remain to be answered, and some of them are discussed in the present paper.
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PMID:Regulation of different proteolytic pathways in skeletal muscle in fasting and diabetes mellitus. 808 98

Yeast fatty acid synthase consists of two independent polypeptide strains, alpha and beta. The functional multienzyme complex, composed of six alpha- and six beta-subunits, is rather stable against proteolysis in vivo. Mutations in one of the subunits or deletion of one subunit lead to degradation of the nonmutated remaining fatty acid synthase protein. We show that the unassembled alpha-subunit of this enzyme is short-lived, and degradation depends on the presence of active cytoplasmic proteinase yscE, the yeast proteasome. The unassembled beta-subunit is degraded by a nonvacuolar proteolytic system under vegetative growth conditions. However, starvation of a vacuolar proteinase mutant strain, which lacks the alpha-subunit of fatty acid synthase, leads to appearance of the unassembled beta-subunit is isolated vacuoles. This indicates that the major vacuolar peptidases proteinase yscA and yscB are at least partly involved in degradation of the beta-subunit of fatty acid synthase. In a proteinase yscA and yscB double mutant strain wild type for fatty acid synthase both subunits of fatty acid synthase, alpha and beta, are detectable in vacuoles. In addition, under the same starvation conditions other cytoplasmic proteins are found in the vacuole of a proteinase yscA and yscB double mutant strain. The experiments in conjunction with the previous finding of the appearance of vesicles in vacuoles of starved cells (Simeon, A., van der Klei, I.J., Veenhuis, M., and Wolf, D. H. (1992) FEBS Lett. 301, 231-235) indicate that transport of these tested cytoplasmic proteins into the vacuole is an unselective bulk process induced by nutritional stress.
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PMID:Tracing intracellular proteolytic pathways. Proteolysis of fatty acid synthase and other cytoplasmic proteins in the yeast Saccharomyces cerevisiae. 826 67

Sp1 is a ubiquitously expressed transcription factor that is particularly important for the regulation of TATA-less genes that encode housekeeping proteins. Most growth factors and receptors are also encoded by such genes. Sp1 is multiply O glycosylated by covalent linkage of the monosaccharide N-acetylglucosamine (O-GlcNAc) to serine and threonine residues. Based on an earlier observation that growth factor gene transcription can be regulated by glucose and glucosamine in vascular smooth muscle cells, we determined whether Sp1 glycosylation could be regulated and if this modification altered Sp1 function. We found that Sp1 becomes hyperglycosylated when cells are exposed to 5 mM glucosamine, whereas under glucose starvation, stimulation with cyclic AMP (cAMP) results in nearly complete deglycosylation of this protein. Correlating with this hypoglycosylated state, Sp1 is rapidly proteolytically degraded by an enzyme(s) that can be inhibited by specific proteasome inhibitors, lactacystin and LLnL. Treatment of cells with glucose or glucosamine protects Sp1 from cAMP-mediated degradation, whereas blockade of glucosamine synthesis abrogates glucose but not glucosamine protection. This effect on Sp1 is specific, in that the Stat-3 and E2F transcription factors did not undergo degradation under these conditions. The O-GlcNAc modification of Sp1 may play a role as a nutritional checkpoint. In the absence of adequate nutrition, Sp1 becomes hypoglycosylated and thereby subject to proteasome degradation. This process could potentially result in reduced general transcription, thereby conserving nutrients.
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PMID:Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. 911 24

Covalent attachment of Candida utilis cells, possibly simulating natural microbial immobilizations, stimulated stable and significant enhancement of extracellular production of alkaline protease, specifically induced by four different starvation conditions. The enzyme analysis confirmed the identity of the proteases released under all conditions of starvation and no parallel production of other proteolytic enzyme. The enhancement phenomenon as a uniform and stable effect of the whole cell immobilization is discussed in relation to the effect of multipoint, cell-solid surface contact, potentially bringing positive modulations of complex, cellular functions.
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PMID:Changes in the starvation response through covalent cell attachment. 919 12

Degradation of a protein via the ubiquitin proteolytic pathway involves two successive steps. Covalent attachment of ubiquitin to the target protein and degradation of the tagged substrate by the 26S proteasome. Most native cellular proteins that are targeted by the ubiquitin system are short-lived transcriptional activators and growth and cell cycle regulators, as well as unstable membrane proteins. In the present study we demonstrate the involvement of the system in the degradation of tyrosine aminotransferase (TAT), a key enzyme in intermediary metabolism. In vitro, we have shown that the native enzyme is conjugated and degraded in a system that requires ATP and ubiquitin. Degradation was monitored by following the decrease of catalytic activity as well as disappearance of the protein molecule. The enzyme could be protected from degradation by association with its specific cofactor, pyridoxal phosphate (PLP). In vivo, we prepared cell extracts from livers of animals in which TAT was induced by starvation and corticosteroid administration. The dramatic increase in the level of the enzyme was accompanied by a concomitant increase in the level of specific TAT-ubiquitin adducts.
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PMID:Ubiquitin-mediated degradation of tyrosine aminotransferase (TAT) in vitro and in vivo. 922 77

Cyclin D1, a critical positive regulator of G1 progression, has been implicated in the pathogenesis of certain cancers. Regulation of cyclin D1 occurs at the transcriptional and posttranscriptional level. Here we present evidence that cyclin D1 levels are regulated at the posttranscriptional level by the Ca2+-activated protease calpain. Serum starvation of NIH 3T3 cells resulted in rapid loss of cyclin D1 protein that was completely reversible by calpain inhibitors. Actinomycin D and lovastatin induced rapid loss of cyclin D1 in prostate and breast cancer cells that was reversible by calpain inhibitors and not by phenylmethylsulfonyl fluoride, caspase inhibitors, or lactacystin, a specific inhibitor of the 26 S proteasome. Treatment of intact NIH 3T3, prostate, and breast cancer cells with a calpain inhibitor dramatically increased the half-life of cyclin D1 protein. Addition of purified calpain to PC-3-M lysates resulted in Ca2+-dependent cyclin D1 degradation. Transient expression of the calpain inhibitor calpastatin increased cyclin D1 protein in serum-starved NIH 3T3 cells. Cyclins A, E, and B1 have been reported to be regulated by proteasome-associated proteolysis. The data presented here implicate calpain in cyclin D1 posttranslational regulation.
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PMID:Regulation of cyclin D1 by calpain protease. 935 8


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