Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis is associated with a pronounced catabolic response in skeletal muscle, mainly reflecting degradation of the myofibrillar proteins actin and myosin. Recent studies suggest that sepsis-induced muscle proteolysis may reflect ubiquitin-proteasome-dependent protein breakdown. An apparently conflicting observation is that the ubiquitin-proteasome pathway does not degrade intact myofibrils. Thus, it is possible that actin and myosin need to be released from the myofibrils before they can be ubiquitinated and degraded by the proteasome. We tested the hypothesis that sepsis results in disruption of Z-bands, increased expression of calpains, and calcium-dependent release of myofilaments in skeletal muscle. Sepsis induced in rats by cecal ligation and puncture resulted in increased gene expression of micro-calpain, m-calpain, and p94 and in Z-band disintegration in the extensor digitorum longus muscle. The release of myofilaments from myofibrillar proteins was increased in septic muscle. This response to sepsis was blocked by treating the rats with dantrolene, a substance that inhibits the release of calcium from intracellular stores to the cytoplasm. The present results provide evidence that sepsis is associated with Z-band disintegration and a calcium-dependent release of myofilaments in skeletal muscle. Release of myofilaments may be an initial and perhaps rate-limiting component of sepsis-induced muscle breakdown.
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PMID:Sepsis stimulates release of myofilaments in skeletal muscle by a calcium-dependent mechanism. 1042 67

Previous work has shown that chicken strains selected for growth (broilers) degrade muscle proteins less rapidly than those selected for egg laying. They also have decreased calpain and increased calpastatin content in breast muscle. This study aimed to test the hypothesis that these differences correlate with changes in the ATP- and ubiquitin-dependent proteolytic system. Chickens of a broiler strain (Ross 1) and a layer strain (ISABrown) were reared to the age of 4 wk under identical conditions with ad libitum access to feed and water. Mean fractional growth rates were 10.4%/d for broilers and 7.4%/d for layers. Feed intake measured in the last week of the trial was slightly greater in layer birds (.11 and .12 g x g body weight(-1) x d(-1) for broilers and layers respectively; P < .006). Polyubiquitin (UbI) messenger RNA was abundant in the muscles of these well-fed birds, but it showed little difference between strains. Muscle did not significantly express the UbII polyubiquitin gene. The ATP-dependent system conjugating ubiquitin to endogenous proteins had greatest activity in the gastrocnemius muscle of broiler birds but was not significantly different between breeds. Proteins cross-reactive with antisera to recombinant human proteasome regulatory subunits MSS1 (multicopy suppressor of SUG 1; S7) and TBP1 (tat binding protein 1; S6') were present in muscle homogenates from both strains of bird. The chick equivalent of TBP1 was more abundant in breast muscle of broiler birds than in leg muscle, or in either muscle of layers. Antiserum to recombinant yeast subunit mts2 (mitosis temperature sensitive gene 2; S4) did not react with any protein of the expected size but detected a 30-kDa peptide that was not associated with the 26S proteasome; this was found only in muscle from the layer strain. Hence, during normal growth of chickens, rates of protein degradation are not controlled by the expression of ubiquitin mRNA or the conjugation of ubiquitin. However, the composition of the 26S proteasome may be a regulatory factor.
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PMID:Ubiquitin gene expression and ubiquitin conjugation in chicken muscle do not reflect differences in growth rate between broiler and layer birds. 1043 15

The purpose of this article is to review evidence that the ubiquitin-proteasome proteolytic pathway plays an important role in injury- and sepsis-induced muscle catabolism. Such evidence includes upregulated gene expression of several of the components of the ubiquitin-proteasome pathway as well as energy-dependency of the injury- and sepsis-induced muscle protein breakdown. Although the ubiquitin-proteasome pathway is the predominant mechanism of muscle breakdown in various catabolic conditions, other proteolytic mechanisms, in particular calcium-dependent, calpain-mediated protein degradation, probably participate as well.
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PMID:Pathways of muscle protein breakdown in injury and sepsis. 1045 47

The proteasome regulates cellular processes as diverse as cell cycle progression and NF-kappaB activation. In this study, we show that the potent antitumor natural product epoxomicin specifically targets the proteasome. Utilizing biotinylated-epoxomicin as a molecular probe, we demonstrate that epoxomicin covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome. Enzymatic analyses with purified bovine erythrocyte proteasome reveal that epoxomicin potently inhibits primarily the chymotrypsin-like activity. The trypsin-like and peptidyl-glutamyl peptide hydrolyzing catalytic activities also are inhibited at 100- and 1,000-fold slower rates, respectively. In contrast to peptide aldehyde proteasome inhibitors, epoxomicin does not inhibit nonproteasomal proteases such trypsin, chymotrypsin, papain, calpain, and cathepsin B at concentrations of up to 50 microM. In addition, epoxomicin is a more potent inhibitor of the chymotrypsin-like activity than lactacystin and the peptide vinyl sulfone NLVS. Epoxomicin also effectively inhibits NF-kappaB activation in vitro and potently blocks in vivo inflammation in the murine ear edema assay. These results thus define epoxomicin as a novel proteasome inhibitor that likely will prove useful in exploring the role of the proteasome in various in vivo and in vitro systems.
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PMID:Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. 1046 20

Regulation of estrogen receptor (ER) concentration is a key component in limiting estrogen responsiveness in target cells. Yet the mechanisms governing ER concentration in the lactotrope cells of the anterior pituitary, a major site of estrogen action, are undetermined. In this study, we used a lactotrope cell line, PR1, to explore regulation of ER protein by estrogen. Estrogen treatment resulted in an approximate 60% decrease in ER steady state protein levels. Suprisingly, the decline in ER protein was apparent within 1 h of estrogen treatment and occurred in the absence of protein synthesis and transcription. Direct regulation of ER protein was further confirmed by pulse chase analysis, which showed that ER protein half-life was shortened from greater than 3 h to 1 h in the presence of estrogen. The estrogen-induced degradation of ER protein could be prevented by pretreatment with peptide aldehyde inhibitors of proteasome protease whereas inhibitors of calpain and lysosomal proteases were ineffective. Inhibition of proteasome activity maintained ER protein at a level equivalent to control cells not stimulated with estrogen but increased estrogen-binding activity by 1.75-fold. Proteolytic regulation of ER by the proteasome is not limited to pituitary lactotrope cells but is also operational in MCF-7 breast cancer cells, suggesting that this may be a common regulatory pathway used by estrogen. These studies describe a nongenomic action of estrogen that involves nuclear ER: rapid proteolysis of ER protein via a proteasome-mediated pathway.
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PMID:Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. 1047 43

P-glycoprotein (Pgp) is a plasma-membrane glycoprotein that confers multi-drug resistance (MDR) on cells and displays ATP-driven drug pumping. The possible contribution of calpain-mediated proteolytic pathways to the functional regulation of the Pgp molecule was evaluated using K562/DXR, MDR cells. N-Acetyl-L-leucyl-L-leucyl-norleucinal was effluxed by Pgp, but N-benzyloxycarbonyl-L-leucyl-L-leucinal (zLLal), an inhibitor of calpain, retarded the degradation of Pgp leading to accumulation of the molecule largely at the cell surface membrane. Treatment with brefeldin A did not obstruct the zLLal-induced Pgp accumulation. NH4Cl increased the cytoplasmic Pgp level, with a slight to significant decrease at the cell surface membrane. Ubiquitin-ELISA and western blot analysis confirmed that the Pgp molecule, which accumulated mainly at the cell surface, was ubiquitinated. However, lactacystin did not show any accumulation of Pgp in either the cytoplasm or the cell surface membrane, suggesting that the proteasome did not participate in the phenomenon. Additionally, the Pgp was limitedly proteolyzed by calpain into two 98 kDa and 69 kDa, fragments within one minute. Despite the increased accumulation of Pgp at the cell surface after treatment with calpain inhibitor, the cytoplasmic doxorubicin level of the cells treated with a calpain inhibitor was higher than that of non-treated cells and approached that of parental cells. These results indicated that calpain involved Pgp turnover and that calpain inhibition induced ubiquitinated Pgp-accumulation mainly at the cell surface membrane with a reduction in its own functions suggesting that the modulation of Pgp-turnover involves MDR-reversal by another approach.
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PMID:Calpain inhibitor causes accumulation of ubiquitinated P-glycoprotein at the cell surface: possible role of calpain in P-glycoprotein turnover. 1049 48

To elucidate the factors affecting endothelial susceptibility to apoptosis, we studied the effects of cell density on endothelial cell apoptosis induced by deprivation of serum and fibroblast growth factor-2 (FGF-2/basic FGF). On deprivation, more cells became apoptotic in a dense culture (5 x 10(2) cells/mm(2)) than in a sparse culture (1 x 10(2) cells/mm(2)) of human umbilical vein endothelial cells. FGF-2, hepatocyte growth factor, and vascular endothelial cell growth factor, but not insulin-like growth factor-I, decreased apoptosis in the dense culture to a level similar in the sparse culture. An anti-FGF-2 antibody significantly increased the apoptosis in the sparse culture, suggesting that the sparse culture was resistant to apoptosis because of the greater autocrine production of FGF-2. Western blot analysis and metabolic labeling revealed that the sparse culture has, in fact, more FGF-2 than the dense culture. The steady state level of mRNA for FGF-2 was not significantly different between the dense and sparse cultures. Among a panel of inhibitors for 2 major cytoplasmic proteolytic enzymes, calpain inhibitors increased FGF-2 in the dense culture, but proteasome inhibitors did not. Our findings demonstrate that cell density affects endothelial survival by regulating autocrine FGF-2 production through a calpain inhibitor-sensitive mechanism.
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PMID:Autocrine FGF-2 is responsible for the cell density-dependent susceptibility to apoptosis of HUVEC : A role of a calpain inhibitor-sensitive mechanism. 1052 60

Polypeptide sequences enriched in proline (P), glutamate (E), serine (S), and threonine (T), dubbed PEST domains, are proposed to expedite the degradation of proteins. The proteolysis of one PEST-containing protein, IkappaBalpha, is prerequisite to the activation of the transcription factor NF-kappaB. Two mechanisms of IkappaBalpha degradation in vivo have been described, one well characterized through the ubiquitin-proteasome pathway, and another less characterized through calpain. In this report, a mutational analysis was done to identify any regions of IkappaBalpha that facilitate its recognition and proteolysis by calpain in vitro. These studies revealed that the PEST sequence of IkappaBalpha is critical for its calpain-dependent degradation. Furthermore, the IkappaBalpha-PEST domain binds to the calmodulin-like domain of the large subunit of mu-calpain (muCaMLD). Transfer of the IkappaBalpha-PEST domain to a protein incapable of either binding to or being degraded by mu-calpain allowed for the interaction of the chimeric protein with muCaMLD and resulted in its susceptibility to calpain proteolysis. Moreover, the muCaMLD of calpain acts as a competitive inhibitor of calpain-dependent IkappaBalpha degradation. Our data demonstrate that the IkappaBalpha-PEST sequence acts as a modular domain to promote the physical association with and subsequent degradation by mu-calpain and suggest a functional role for PEST sequences in other proteins as potential calpain-targeting units.
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PMID:The PEST domain of IkappaBalpha is necessary and sufficient for in vitro degradation by mu-calpain. 1052 80

p107 protein, a member of the retinoblastoma family protein, suppresses growth promotion in cancer cells. We have already reported evidence that calpain, a calcium dependent protease is involved in the cleavage of p107 protein. We show here that p107 protein can also be a substrate for ubiquitination. A negative growth regulator, the HMG-CoA reductase inhibitor lovastatin was found to induce loss of p107 protein which was reversible by a specific protease inhibitor lactacystin as well as calpain inhibitor. Following treatment with lovastatin higher molecular weight ubiquitinated forms of p107 were detected by anti-p107 immunoprecipitation and anti-ubiquitin Western blotting. These forms further increased when lactacystin was added to culture medium. These results indicate that ubiquitin-proteasome pathway plays a potential role in the degradation as well as calpain. The data presented here suggest a model in which calpain and ubiquitin-proteasome system possibly play a cooperative role in targeting the protein under certain conditions.
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PMID:Proteolytic degradation of the retinoblastoma family protein p107: A putative cooperative role of calpain and proteasome. 1053 70

Peroxidases of the peroxiredoxin (Prx) family catalyze the reduction of H(2)O(2) and lipid peroxides. The effects of H(2)O(2), 12-O-tetradecanoylphorbol 13-acetate (TPA), and silica on the abundance of two cytosolic isoforms of Prx (PrxI and PrxII) were examined in Rat2 cells. TPA induces the production of reactive oxygen species (ROS) in various mammalian cell types, and silica induces the production of ROS in Rat2 cells. Whereas H(2)O(2) and TPA did not affect the concentration of PrxI or Prx II, silica triggered a rapid degradation of both Prx enzymes. Silica also induced degradation of the NF-kappaB inhibitor IkappaB-alpha. N-Acetylcysteine and diphenyleneiodonium, both of which inhibit the accumulation of intracellular ROS, each blocked silica-induced degradation of IkappaB-alpha but had no effect on that of the Prx enzymes, suggesting that ROS do not contribute to Prx proteolysis. The silica-induced degradation of Prx enzymes was also insensitive to the proteasome inhibitors MG132 and lactacystin, whereas IkappaB-alpha proteolysis was completely blocked by these inhibitors. Experiments with the Ca(2+) ionophore A23187 indicated that a Ca(2+)-dependent protease such as calpain might contribute substantially to silica-induced degradation of PrxII, but only moderately to that of PrxI. These results indicate that silica increases cellular oxidative stress not only by inducing ROS production, but also by triggering the degradation of Prx enzymes that are responsible for elimination of cellular ROS. Such aggravated oxidative stress might be important in the initial pathogenesis of silica-associated pulmonary diseases.
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PMID:Rapid degradation of PrxI and PrxII induced by silica in Rat2 cells. 1055 5


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