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

---

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

The 20S proteasome (prosome) is a highly organized multiprotein complex with approximate molecular weight of about 700 kDa. Whilst the role of the proteasome in the processing and turnover of cellular proteins is becoming clearer, its relationship with RNA remains still obscure. Here we focus on the nature and function of proteasome associated endonuclease activity. Thus the involvement of a proteasome alpha-type subunit in RNA-degradation, the catalytic requirements, the interaction of proteasomes with their RNA-substrate and the identification of a well defined cleavage site in the 3'UTR of short-lived cellular mRNAs will be described in detail. All data indicate that proteasomes associated endonuclease activity could be involved in post-transcriptional gene control at the level of translation.
...
PMID:Proteasome (prosome) associated endonuclease activity. 922 91

A hairpin ribozyme, RzCR2A, directed against position 323 of the hepatitis C virus 5'-untranslated region (HCV 5'-UTR) was used to establish and validate a novel method for the detection of cellular target molecules for hairpin ribozymes, termed C-SPACE (cleavage-specific amplification of cDNA ends). For C-SPACE, HeLa mRNA containing the transcript of interest was subjected to in vitro cleavage by RzCR2A in parallel with a control ribozyme, followed by reverse transcription using a modified SMART cDNA amplification method and cleavage-specific PCR analysis. C-SPACE allowed identification of the RzCR2A target transcript from a mixture containing the entire cellular mRNA while only requiring knowledge of the ribozyme binding sequence for amplification. In a similar approach, C-SPACE was used successfully to identify human 20S proteasome alpha-subunit PSMA7 mRNA as the cellular target RNA of Rz3'X, a ribozyme originally designed to cleave the negative strand HCV 3'-UTR. Rz3'X was found to substantially inhibit HCV internal ribosome entry site (IRES) activity and PSMA7 was subsequently confirmed to be involved in HCV IRES-mediated translation. Thereby, C-SPACE was validated as a powerful tool to rapidly identify unknown target RNAs recognized and cleaved by hairpin ribozymes.
...
PMID:C-SPACE (cleavage-specific amplification of cDNA ends): a novel method of ribozyme-mediated gene identification. 1157 96

We have partially reconstituted 20S proteasome/RNA complexes using oligonucleotides corresponding to ARE (adenosine- and uridine-rich element) (AUUUA)4 and HIV-TAR (human immunodeficiency virus-Tat transactivation response element), a stem-loop structure in the 5' UTR (untranslated region) of HIV-mRNAs. We demonstrate that these RNAs which associate with proteasomes are degraded by proteasomal endonuclease activity. The formation of these 20S proteasome/RNA substrate complexes is rather specific since 20S proteasomes do not interfere with truncated TAR that is not cleaved by proteasomal endonuclease. In addition, affinity of proteasomes for (AUUUA)4 is much stronger as it is for HIV-TAR. These results provide further arguments for our hypothesis that proteasomes could be involved in the destabilisation of cytokines mRNAs containing AUUUA sequences as well as viral mRNAs.
...
PMID:Substrate affinity and substrate specificity of proteasomes with RNase activity. 1268 29

Mcl-1 is an antiapoptotic member of the Bcl-2 family whose protein and mRNA have a short half-life. In this report, we studied the changes in Mcl-1 protein and mRNA expression induced by staurosporine and aspirin. Both drugs induced apoptosis in Jurkat cells and reduced the levels of Mcl-1 protein. The caspase inhibitor Z-VAD.fmk and the proteasome inhibitor MG132 partially protected Mcl-1 from decay, indicating that both caspase-dependent and proteasome pathways are involved during apoptosis. Staurosporine also reduced Mcl-1 mRNA levels and this reduction was mostly caspase-dependent. In addition, staurosporine reduced the transcriptional activity of the Mcl-1 promoter fused to a luciferase gene reporter more than actinomycin D, a general inhibitor of transcription. Thus, we conclude that staurosporine down-regulates Mcl-1 mRNA levels by inhibiting transcription in a caspase-dependent manner and reduces Mcl-1 protein levels by a caspase-independent post-transcriptional mechanism. In contrast aspirin, at doses and times that induced loss of viability and decay of Mcl-1 protein, had no effect on Mcl-1 mRNA levels. Aspirin rapidly inhibited de novo protein synthesis before caspase activation. Moreover, the translational factor eIF2alpha was transiently phosphorylated and therefore inhibited very soon after aspirin treatment. Aspirin also inhibited the luciferase reporter activity of several attached promoter constructs, but it did not affect the luciferase activity of a construct containing an internal ribosome entry site (IRES) in its mRNA 5(')UTR. We conclude that staurosporine inhibits transcription and translation, whereas aspirin only inhibits cap-dependent translation. Treatment with cycloheximide, at doses that inhibit protein synthesis without affecting cell viability, also induced Mcl-1 protein decay. Mcl-1 disappearance might be necessary but not sufficient for the induction of apoptosis by staurosporine and aspirin. A model for the control of Mcl-1 during drug-induced apoptosis is presented.
...
PMID:Transcriptional and translational control of Mcl-1 during apoptosis. 1294 Dec 95

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide expressed in the vascular endothelium. Stringent control over ET-1 expression is achieved through a highly regulated promoter and rapid mRNA turnover. Since little is known about mechanisms governing ET-1 post-transcriptional regulation, and changes in ET-1 mRNA stability are implicated in disease processes, we characterized these pathways using a variety of functional approaches. We expressed human ET-1 and luciferase transcripts with or without a wild type ET-1 3'-untranslated region (3'-UTR) and found that the 3'-UTR had potent mRNA destabilizing activity. Deletion analysis localized this activity to two domains of the 3'-UTR we have termed destabilizing elements 1 and 2 (DE1 and DE2). Mutational studies revealed that DE1 functions as an AU-rich element (ARE) dependent on a 100-nucleotide region. This activity was further localized to a 10-nucleotide region at position 978-987 of the 3'-UTR. Depletion of AUF1 by RNA interference up-regulated ET-1 in endothelial cells suggesting AUF1-dependent regulation. Since AUF1 functions through the ubiquitin-proteasome pathway, we disrupted this pathway with heat shock and proteasome inhibitor in endothelial cells and observed stabilization of endogenous ET-1 mRNA. Chimeric transcripts bearing wild type ET-1 3'-UTRs were also stabilized in response to proteasome inhibition whereas DE1 mutants failed to respond. Taken together, these findings suggest a complex model of ARE-mediated mRNA turnover dependent on two 3'-UTR domains, DE1 and DE2. Furthermore, DE1 functions as an ARE directing mRNA half-life through the proteasome. Finally, this data provides evidence for a novel pathway of ET-1 mRNA stabilization by heat shock.
...
PMID:Role of the 3'-untranslated region of human endothelin-1 in vascular endothelial cells. Contribution to transcript lability and the cellular heat shock response. 1466 Jun 16

Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of inflammation. TNF-alpha expression is regulated by transcriptional and post-transcriptional mechanisms, including mRNA stability and translation. Post-transcriptional control operates through cis-elements in the 3' Untranslated-Region of the TNF-alpha mRNA to which trans-acting proteins bind. One of the best characterized trans-acting proteins is Tristetraprolin (TTP), which regulates TNF-alpha message stability. However, the precise mechanisms controlling TNF-alpha message stability are unclear, with data supporting a role for the proteasome, the exosome, and the RNA processing-body (P-body), as well as the involvement of the microRNAs. We examined the effect of proteasome inhibition on endogenous TNF-alpha mRNA stability, TNF-alpha 3'UTR reporter expression and TTP function in the RAW264.7 cells. These data establish that proteasome inhibition stabilized endogenous TNF-alpha mRNA, increased TTP protein levels but inhibited TTP mediated TNF-alpha mRNA decay. Importantly, proteasome inhibition stabilized the TNF-alpha message to the same degree as LPS stimulation. To further characterize the control of TTP function, we examined the combinatorial effect of p38, ERK and JNK activation on TNF-alpha post-transcriptional expression and TTP function. These data establish that TTP mediated TNF-alpha mRNA decay is inhibited by the combined activation of ERK and p38 and not by p38 activation alone. The combined activation of ERK/p38 was sufficient to stabilize endogenous TNF-alpha mRNA to the same degree as LPS stimulation. Together these data indicate that the proteasome is a critical control point for TTP mediated TNF-alpha mRNA decay and activation of both ERK and p38 is required to inhibit TTP function and stabilize TNF-alpha mRNA.
...
PMID:Tristetraprolin regulates TNF TNF-alpha mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. 1760 94

Glutathione peroxidase-3 (GPx-3) is a key antioxidant enzyme in the plasma. GPx-3 was previously identified as the major antioxidative enzyme that was induced upon nontoxic proteasome inhibition in endothelial cells. Here, we investigated the determinants of the proteasome inhibitor-induced expression of GPx-3. Nontoxic proteasome inhibition massively upregulates GPx-3 RNA and protein in human umbilical cord vein cells within 24 h. Surprisingly, induction of GPx-3 was species-specific for human cells. The exponential upregulation of GPx-3 is mediated by transcriptional activation of the human GPx-3 promoter and, in addition, stabilization of GPx-3 mRNA: in reporter gene assays with full-length and deleted variants of the human GPx-3 promoter we identified a putative antioxidative response element (ARE) as essential and also sufficient for transcriptional activation of GPx-3 by proteasome inhibition. However, the ARE-specific antioxidative transcription factor Nrf2 is not involved in the activation of GPx-3. UV-crosslinking using the 3'UTR of GPx-3 revealed an altered protein binding pattern in the presence of proteasome inhibitors, thus indicating regulation of mRNA stability of human GPx-3. As GPx-3 is secreted into the plasma, our data point toward a borderline defense mechanism of endothelial cell-derived GPx-3 to protect the vasculature from oxidative stress.
...
PMID:Human-specific induction of glutathione peroxidase-3 by proteasome inhibition in cardiovascular cells. 1976 14

Cyclooxygenases (COX-1 and COX-2) are ER-resident proteins that catalyze the committed step in prostanoid synthesis. COX-1 is constitutively expressed in many mammalian cells, whereas COX-2 is usually expressed inducibly and transiently. Abnormal expression of COX-2 has been implicated in the pathogenesis of chronic inflammation and various cancers; therefore, it is subject to tight and complex regulation. Differences in regulation of the COX enzymes at the posttranscriptional and posttranslational levels also contribute significantly to their distinct patterns of expression. Rapid degradation of COX-2 mRNA has been attributed to AU-rich elements (AREs) at its 3' UTR. Recently, microRNAs that can selectively repress COX-2 protein synthesis have been identified. The mature forms of these COX proteins are very similar in structure except that COX-2 has a unique 19-amino acid (19-aa) segment located near the C-terminus. This C-terminal 19-aa cassette plays an important role in mediation of the entry of COX-2 into the ER-associated degradation (ERAD) system, which transports ER proteins to the cytoplasm for degradation by the 26S proteasome. A second pathway for COX-2 protein degradation is initiated after the enzyme undergoes suicide inactivation following cyclooxygenase catalysis. Here, we discuss these molecular determinants of COX-2 expression in detail. [BMB reports 2009; 42(9): 552-560].
...
PMID:Posttranscriptional and posttranslational determinants of cyclooxygenase expression. 1978 55

Aberrant messenger RNAs containing a premature termination codon (PTC) are eliminated by the nonsense-mediated mRNA decay (NMD) pathway. Here, we show that a crucial NMD factor, up frameshift 1 protein (Upf1), is required for rapid proteasome-mediated degradation of an aberrant protein (PTC product) derived from a PTC-containing mRNA. Western blot and pulse-chase analyses revealed that Upf1 stimulates the degradation of specific PTC products by the proteasome. Moreover, the Upf1-dependent, proteasome-mediated degradation of the PTC product was also stimulated by mRNAs harbouring a faux 3' untranslated region (3'-UTR). These results indicate that protein stability might be regulated by an aberrant mRNA 3'-UTR.
...
PMID:Upf1 stimulates degradation of the product derived from aberrant messenger RNA containing a specific nonsense mutation by the proteasome. 1979 2

Strong evidence has shown that a defect in the Parkin gene is known to be a common, genetic cause of Parkinson disease (PD). The E3 ubiquitin ligase Nrdp1 is shown to interact with the N terminal of Parkin (the first 76 amino acids) and catalyze degradation of Parkin via the ubiquitin-proteasome pathway, suggesting that Nrdp1 may be involved in the development of PD via the regulation of Parkin, We believe we are the first to have screened PD patients for mutations in the Nrdp1 gene to determine the association between these variants and PD. By direct sequencing, we analysed the entire coding regions and 5' UTR of Nrdp1 in 209 Chinese PD patients and 302 unrelated healthy individuals. No variant was detected in the coding regions (exons 3-7); only 2 variants (c.-206 T > A and c.-208-8 A > G) were identified in the 5' UTR (exon 2) and intron 1. Furthermore, a study of the allelic and genotypic association between patients and controls showed no significant association between the c.-206 T > A polymorphism and PD; c.-208-8 A > G was identified in one PD patient and not in controls. Our data do not support the hypothesis of a major role for the Nrdp1 gene in PD development in the Chinese population.
...
PMID:Genetic screening for mutations in the Nrdp1 gene in Parkinson disease patients in a Chinese population. 1980 Aug 34


1 2 3 4 5 Next >>

---