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: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Butyrate, a 4-carbon fatty acid, has been shown to cause growth arrest and apoptosis of cancer cells in vitro and in vivo. The signaling pathways leading to changes in cell growth are unclear. We used a functional proteomics approach to delineate the pathways and mediators involved in butyrate action in HT-29 cells at 24 hr posttreatment. Using 2-dimensional gel electrophoresis, we showed that butyrate treatment resulted in alterations in the proteome of HT-29 cells. MALDI-TOF mass spectrometry was used to identify butyrate-regulated spots. First, our results revealed that the expression of various components of the ubiquitin-proteasome system was altered with butyrate treatment. This suggests that, in addition to the regulation of gene expression through the histone deacetylase pathway, proteolysis could be a means by which butyrate may regulate the expression of key proteins in the control of cell cycle, apoptosis and differentiation. Second, we found that both proapoptotic proteins (capase-4 and cathepsin D) and antiapoptotic proteins (hsp27, antioxidant protein-2 and pyruvate dehydrogenase E1) were simultaneously upregulated in butyrate-treated cells. Western blotting was carried out to confirm butyrate regulation of the spots. Both cathepsin D and hsp27 showed a time-dependent increase in expression with butyrate treatment in HT-29 cells. However, in HCT-116 cells, which were 5-fold more sensitive to butyrate-induced apoptosis, the upregulation of cathepsin D with time was not accompanied by a similar increase in hsp27 levels. Thus, the simultaneous upregulation of both proapoptotic and antiapoptotic proteins in HT-29 cells may account for their relative resistance to butyrate-induced apoptosis.
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PMID:Proteome analysis of butyrate-treated human colon cancer cells (HT-29). 1192 Jun 11

There is little information on the mechanisms responsible for muscle recovery following a catabolic condition. To address this point, we reloaded unweighted animals and investigated protein turnover during recovery from this highly catabolic state and the role of proteolysis in the reorganization of the soleus muscle. During early recovery (18 h of reloading) both muscle protein synthesis and breakdown were elevated (+65%, P<0.001 and +22%, P<0.05, respectively). However, only the activation of non-lysosomal and Ca(2+)-independent proteolysis was responsible for increased protein breakdown. Accordingly, mRNA levels for ubiquitin and 20S proteasome subunits C8 and C9 were markedly elevated (from +89 to +325%, P<0.03) and actively transcribed as shown by the analysis of polyribosomal profiles. In contrast, both cathepsin D and 14-kDa-ubiquitin conjugating enzyme E2 mRNA levels decreased, suggesting that the expression of such genes is an early marker of reversed muscle wasting. Following 7 days of reloading, protein synthesis was still elevated and there was no detectable change in protein breakdown rates. Accordingly, mRNA levels for all the proteolytic components tested were back to control values even though an accumulation of high molecular weight ubiquitin conjugates was still detectable. This suggests that soleus muscle remodeling was still going on. Taken together, our observations suggest that enhanced protein synthesis and breakdown are both necessary to recover from muscle atrophy and result in catch-up growth. The observed non-coordinate regulation of proteolytic systems is presumably required to target specific classes of substrates (atrophy-specific protein isoforms, damaged proteins) for replacement and/or elimination.
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PMID:Regulation of proteolysis during reloading of the unweighted soleus muscle. 1267 58

Abnormal proteolysis may be involved in the motor neuron degeneration of amyotrophic lateral sclerosis (ALS). Although several studies of the ubiquitin-proteasome system in ALS have been reported, the endosome-lysosome system has not been investigated in detail. To clarify the association of neurodegeneration with the endosome-lysosome system in ALS, we examined the pathological expression of cysteine proteases such as cathepsins B, H and L and an aspartate protease, cathepsin D, in the anterior horns of 15 ALS cases and 5 controls. In the ALS cases, cathepsin B immunoreactivity was preferentially decreased in the lateral parts of the anterior gray horns compared with the controls. Its immunoreactivity was increased in the cytoplasm of both shrunken and pigmented neurons but was weak in the neurons containing Bunina bodies. In addition, reactive astrocytes were also immunolabeled with cathepsin B. Cathepsin H and cathepsin L were detected in the cytoplasm of a small number of shrunken and pigmented neurons. Cathepsin D immunoreactivity was strong in the cytoplasm of all motor neurons. The immunoreactivity of cathepsins H, L and D was not significantly different between control and ALS cases. Western blot analysis showed that the 25-kDa activated form of cathepsin B was down-regulated in ALS. Our results suggest that cathepsin B is involved in the motor neuron degeneration in ALS.
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PMID:Involvement of cathepsin B in the motor neuron degeneration of amyotrophic lateral sclerosis. 1267 46

Polyglutamine expansion in the N terminus of huntingtin (htt) causes selective neuronal dysfunction and cell death by unknown mechanisms. Truncated htt expressed in vitro produced htt immunoreactive cytoplasmic bodies (htt bodies). The fibrillar core of the mutant htt body resisted protease treatment and contained cathepsin D, ubiquitin, and heat shock protein (HSP) 40. The shell of the htt body was composed of globules 14-34 nm in diameter and was protease sensitive. HSP70, proteasome, dynamin, and the htt binding partners htt interacting protein 1 (HIP1), SH3-containing Grb2-like protein (SH3GL3), and 14.7K-interacting protein were reduced in their normal location and redistributed to the shell. Removal of a series of prolines adjacent to the polyglutamine region in htt blocked formation of the shell of the htt body and redistribution of dynamin, HIP1, SH3GL3, and proteasome to it. Internalization of transferrin was impaired in cells that formed htt bodies. In cortical neurons of Huntington's disease patients with early stage pathology, dynamin immunoreactivity accumulated in cytoplasmic bodies. Results suggest that accumulation of a nonfibrillar form of mutant htt in the cytoplasm contributes to neuronal dysfunction by sequestering proteins involved in vesicle trafficking.
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PMID:Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. 1471 59

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that forms a functional heterodimeric complex with the AhR nuclear translocator (Arnt) protein. The environmental toxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is a high affinity ligand for the AhR and has been extensively used to investigate AhR-mediated biochemical and toxic responses. TCDD modulates several endocrine pathways including inhibition of 17beta-estradiol-induced responses in the immature and ovariectomized rodent uterus and mammary gland and in human breast cancer cell lines. TCDD inhibits formation and growth of mammary tumors in carcinogen-induced rodent models and relatively nontoxic selective AhR modulators (SAhRMs) are being developed for treatment of breast cancer. The mechanisms of inhibitory AhR-estrogen receptor (ER) crosstalk have been investigated in MCF-7 breast cancer cells by analysis of promoter regions of genes induced by E2 and inhibited by TCDD. AhR-mediated inhibition of E2-induced cathepsin D, pS2, c-fos, and heat shock protein 27 gene expression involves direct interaction of the AhR complex with inhibitory pentanucleotide (GCGTG) dioxin responsive elements (iDREs) resulting in disruption of interactions between proteins binding DNA elements required for ER action and the basal transcription machinery. Mechanisms of inhibitory AhR-ER crosstalk indicate that functional iDREs are required for inhibition of some genes; however, results indicate that other interaction pathways are important including AhR-mediated proteasome-dependent degradation of the ER.
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PMID:Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells. 1497 92

It has been shown that large doses of acetaminophen can result in increased degradation of the hepatic cytochrome P450 (CYP) enzymes in vivo; however, the proteolytic pathways have not been identified. We found that incubating transfected HepG2 cells that express CYP3A4 or a reconstituted microsomal model containing human liver microsomes and cytosol, high concentrations of acetaminophen could induce a dose- and time-dependent degradation of CYP3A4. In the microsomal model the degradation could be blocked and augmented by the presence of catalase and superoxide dismutase, respectively. Tocopherol could also protect against the acetaminophen-induced degradation. However, lipid peroxidation assays showed no significant increases in lipid peroxidation products nor was there any protection by propyl gallate. Protease and proteasome inhibitors showed that the proteolytic process was mainly (85%) mediated by the lysosomal pathway, whereas a minor portion (15%) of the degradation was mediated by the proteasomal pathway. Both pepstatin A and anti-cathepsin D neutralizing antibody decreased acetaminophen-induced degradation of CYP3A4 in microsomal model systems. Pepstatin A also blocked the acetaminophen-induced degradation of the CYP3A4 in a transfected HepG2 cell line. Incubating the 3A4 cells in the presence of acetaminophen also increased cathepsin D content and activity. The lysosomal pathway, mainly mediated by cathepsin D, appears to be the major proteolytic pathway involved in the degradation of the P450 enzymes induced by toxic doses of acetaminophen.
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PMID:Characterization of the acetaminophen-induced degradation of cytochrome P450-3A4 and the proteolytic pathway. 1507 44

Estrogen receptor-alpha (ER alpha) is a ligand-dependent transcription factor that mediates physiological responses to 17 beta-estradiol (E2). Ligand binding rapidly down-regulates ER alpha levels through proteasomal proteolysis, but the functional impact of receptor degradation on cellular responses to E2 has not been fully established. In this study, we investigated the effect of blocking the ubiquitin-proteasome pathway on ER alpha-mediated transcriptional responses. In HeLa cells transfected with ER alpha, blocking either ubiquitination or proteasomal degradation markedly increased E2-induced expression of an ER-responsive reporter. Time course studies further demonstrated that blocking ligand-induced degradation of ER alpha resulted in prolonged stimulation of ER-responsive gene transcription. In breast cancer MCF7 cells containing endogenous ER alpha, proteasome inhibition enhanced E2-induced expression of endogenous pS2 and cathepsin D. However, inhibiting the proteasome decreased expression of progesterone receptor (PR), presumably due to the heterogeneity of the PR promoter, which contains multiple regulatory elements. In addition, in endometrial cancer Ishikawa cells overexpressing steroid receptor coactivator 1, 4-hydroxytamoxifen displayed full agonist activity and stimulated ER alpha-mediated transcription without inducing receptor degradation. Collectively, these results demonstrate that proteasomal degradation is not essential for ER alpha transcriptional activity and functions to limit E2-induced transcriptional output. The results further indicate that promoter context must be considered when evaluating the relationship between ER alpha transcription and proteasome inhibition. We suggest that the transcription of a gene driven predominantly by an estrogen-responsive element, such as pS2, is a more reliable indicator of ER alpha transcription activity than a gene like PR, which contains a complex promoter requiring cooperation between ER alpha and other transcription factors.
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PMID:Inhibiting proteasomal proteolysis sustains estrogen receptor-alpha activation. 1528 35

Ubiquitinated inclusions are a common feature of many neurodegenerative conditions. We have proposed that, at least in part, such inclusions may be formed due to dysfunction of the proteasome. We have modeled such proteasomal dysfunction by applying pharmacological inhibitors to cultured embryonic rat cortical neurons. This treatment leads to neuronal death and formation of ubiquitin/alpha-synuclein-positive cytoplasmic inclusions. At late time points following proteasomal inhibition such inclusions are no longer discerned. Instead, many neurons accumulate small ubiquitinated aggregates, which may represent remnants of the inclusions. In this work we have examined a potential mechanism for inclusion dissolution. Electron microscopy images showed activation of macroautophagy at late time points after proteasomal inhibition. Labeling with LysoTracker Red, a dye that accumulates in acidic compartments, or immunostaining for the lysosomal enzyme Cathepsin D, showed an increase in globular staining. Cathepsin D co-localized partially with small ubiquitinated aggregates, but not inclusions. Application of an inhibitor of macroautophagy or of the vacuolar ATPase led to an increase in the number of inclusions and a decrease in small aggregates, whereas an activator of autophagy had the opposite effects. There was no significant change in apoptotic death following these manipulations. We conclude that, following proteasomal inhibition of cultured cortical neurons, there is activation of macroautophagy and of the lysosomal pathway. This activation results in dissolution of ubiquitinated inclusions into small aggregates, without directly impacting neuronal cell death. These data further support the idea that in this model inclusions and neuronal cell death are independent processes.
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PMID:Involvement of macroautophagy in the dissolution of neuronal inclusions. 1532 92

The August Krogh principle, stating that for any particular question in biology, nature holds an ideal study system, was applied by choosing the anorexic, long-distance migration of salmon as a model to analyze protein degradation and amino acid metabolism. Reexamining an original study done over 20 years ago on migrating sockeye salmon (Oncorhynchus nerka), data on fish migration and starvation are reviewed and a general model is developed on how fish deal with muscle proteolysis. It is shown that lysosomal activation and degradation of muscle protein by lysosomal cathepsins, especially cathepsin D and sometimes cathepsin L, are responsible for the degradation of muscle protein during fish migration, maturation and starvation. This strategy is quite the opposite to mammalian muscle wasting, including starvation, uremia, cancer and others, where the ATP-ubiquitin proteasome in conjunction with ancillary systems, constitutes the overwhelming pathway for protein degradation in muscle. In mammals, the lysosome plays a bit part, if any. In contrast, the proteasome plays at best a subordinate role in muscle degradation in piscine systems. This diverging strategy is put into the context of fish metabolism in general, with its high amino acid turnover, reliance on amino acids as oxidative substrates and flux of amino acids from muscle via the liver into gonads during maturation. Brief focus is placed on structure, function and evolution of the key player in fishes: cathepsin D. The gene structure of piscine cathepsin D is outlined, focusing on the existence of duplicate, paralogous, cathepsin D genes in some species and analyzing the relationship between a female and liver-specific aspartyl protease and fish cathepsin Ds. Evolutionary relationships are developed between different groups of piscine cathepsins, aspartyl proteases and other cathepsins. Finally, based on specific changes in muscle enzymes in fish, including migrating salmon, common strategies of amino acid and carbon flux in fish muscle are pointed out, predicting some metabolic concepts that would make ideal application grounds for the August Krogh principle.
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PMID:Salmon spawning migration and muscle protein metabolism: the August Krogh principle at work. 1554 63

Proteome analysis of human umbilical endothelial cells was performed to identify proteins that are modified during vascular endothelial cell growth factor (VEGF)-induced transition from the quiescent into the proliferating-migrative phenotype. Subtractive analysis of two-dimensional gel patterns of human endothelial cells, before and after stimulation with VEGF(165), revealed differences in 85 protein spots. All proteins were identified by peptide sequencing and peptide mass fingerprinting using an electrospray spectrometer. The proteins identified were members of specific families including Ca(2+)-binding proteins, fatty-acid binding proteins, structural proteins, and chaperones. Remarkably, there was a massive activation of cellular machinery for both protein synthesis and protein degradation. Thus, among up-regulated proteins there were members of all groups of heat shock proteins (HSPs; HSP 27, HSP 60, HSP 70p5, HSP 70p8, HSP 90, and HSP 96) and some other proteins showing either chaperone activity or which participate in assembly of multimolecular structures (TCP-1, desmoplakins, junction plakoglobin, GRP 94, thioredoxin related protein, and peptidylprolyl isomerase). The increased expression of HSPs was confirmed at the mRNA level at different stages of treatment with VEGF. Similarly, components of the proteolytic machinery for the degradation of misfolded proteins (ER-60, cathepsin D, proteasome subunits, and protease inhibitor 6) were also up-regulated. On the other hand, changes in the expression of structural proteins (T-plastin, vimentin, alpha tubulin, actin, and myosin) could account, at least in part, for the different morphologies displayed by migrating endothelial cells. In summary, our data show that VEGF levels similar to those during physiological stresses induce a number of genes and multiple endogenous pathways seem to be engaged in restoring cellular homeostasis. To ensure cell survival, the molecular chaperones (the heat shock family of stress proteins) are highly up-regulated providing protein-folding machinery to repair or degrade misfolded proteins.
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PMID:Heat shock proteins and other components of cellular machinery for protein synthesis are up-regulated in vascular endothelial cell growth factor-activated human endothelial cells. 1576 53


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