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)

Inhibitors of proteases are currently emerging as a potential anti-cancer modality. Nonselective protease inhibitors are cytotoxic to leukemia and cancer cell lines and we found that this cytotoxicity is correlated with their potency as inhibitors of the proteasome but not as inhibitors of calpain and cathepsin. Highly selective inhibitors of the proteasome were more cytotoxic and fast-acting than less selective inhibitors (PS341>>ALLN>>ALLM). Induction of wt p53 correlated with inhibition of the proteasome and antiproliferative effect in MCF7, a breast cancer cell line, which was resistant to apoptosis caused by proteasome inhibitors. In contrast, inhibitors of the proteasome induced apoptosis in four leukemia cell lines lacking wt p53. The order of sensitivity of leukemia cells was: Jurkat>HL60> or =U937>>K562. The highly selective proteasome inhibitor PS-341 induced cell death with an IC50 as low as 5 nM in apoptosis-prone leukemia cells. Cell death was preceded by p21WAF1/CIP1 accumulation, an alternative marker of proteasome inhibition, and by cleavage of PARP and Rb proteins and nuclear fragmentation. Inhibition of caspases abrogated PARP cleavage and nuclear fragmentation and delayed, but did not completely prevent cell death caused by PS-341. Reintroduction of wt p53 into p53-null PC3 prostate carcinoma cells did not increase their sensitivity to proteasome inhibitors. Likewise, comparison of parental and p21-deficient cells demonstrated that p21WAF1/CIP1 was dispensable for proteasome inhibitor-induced cytotoxicity. We conclude that accumulation of wt p53 and induction of apoptosis are independent markers of proteasome inhibition.
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PMID:Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. 1091 53

BTG/Tob family proteins, which are characterized by similarities in their N-terminal BTG/Tob homology domains, control cell growth negatively. Among the BTG/Tob family members, BTG2/TIS21/PC3 proteins have been reported to have short lives and to be degraded by the proteasome. However, the mechanisms regulating the stabilities of other BTG/Tob family proteins have not yet been clarified. Here, we report that BTG1, Tob, and Tob2 proteins, as well as BTG2 protein, are degraded by the ubiquitin-proteasome system; the degradation of Tob protein in HeLa cells and the degradation of BTG1, BTG2, Tob and Tob2 proteins transiently expressed in HEK293 cells were inhibited by treatments with proteasome-specific inhibitors. Co-expression of BTG1, BTG2, Tob, or Tob2 protein with ubiquitin in HEK293 cells revealed specific multiubiquitination of each of the four proteins. Although the full-length and N-terminal truncated forms of BTG1, BTG2, Tob, and Tob2 proteins were unstable, the respective C-terminal truncated forms were found to be almost stable, suggesting that the C-terminal regions control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins. In addition, it was found that the respective C-terminal regions confer instability on green fluorescent protein, a normally stable protein. Thus, it can be concluded that the C-terminal regions are necessary and sufficient to control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins.
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PMID:Antiproliferative proteins of the BTG/Tob family are degraded by the ubiquitin-proteasome system. 1213

PMEPA1 was originally identified as a highly androgen-induced gene by serial analysis of gene expression in androgen-treated LNCaP prostate cancer (CaP) cells. PMEPA1 expression is prostate abundant and restricted to prostatic epithelial cells. PMEPA1-encoded protein shows high sequence homology to a mouse N4wbp4-encoded protein that binds to Nedd4 protein, an E3 ubiquitin-protein ligase involved in ubiquitin-dependent, proteasome-mediated protein degradation. Studies from our and other laboratories have suggested the role of PMEPA1 in cell growth regulation as noted by androgen induction of PMEPA1 expression, elevated PMEPA1 expression in nontumorigenic revertants of tumor cell lines after chromosome 8p transfer, and PMEPA1 expression alterations (up- or down-regulation) in human tumors. Here, we demonstrate that PMEPA1 protein through its PY motifs interacts with WW domains of the human NEDD4 protein. Exogenous expression of PMEPA1, in widely used CaP cell lines DU145, PC3, LNCaP, and LNCaP sublines (C4, C4-2, and C4-2B), conferred cell growth inhibition, and at least one of the PY motifs of PMEPA1 may be involved in its cell growth inhibitory functions. Quantitative expression analysis of PMEPA1 in paired normal and tumor cells of 62 patients with primary CaP revealed tumor cells associated decreased expression in 40 of 62 patients that were significantly associated with higher pathologic stage and serum prostate-specific antigen. Taken together, PMEPA1 negatively regulates growth of androgen responsive or refractory CaP cells, and these functions may be mediated through the interaction of PMEPA1 with the NEDD4 protein involved in the ubiquitin-proteasome pathway. Loss or reduced PMEPA1 expression in CaP further suggests for its role in prostate tumorigenesis.
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PMID:PMEPA1, an androgen-regulated NEDD4-binding protein, exhibits cell growth inhibitory function and decreased expression during prostate cancer progression. 1290 94

The MDM2 oncogene has both p53-dependent and p53-independent activities. We have previously reported that antisense MDM2 inhibitors have significant anti-tumor activity in multiple human cancer models with various p53 statuses (Zhang, Z., Li, M., Wang, H., Agrawal, S., and Zhang, R. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 11636-11641). We have also provided evidence that MDM2 has a direct role in the regulation of p21, a cyclin-dependent kinase inhibitor. Here we provide evidence supporting functional interaction between MDM2 and p21 in vitro and in vivo. The inhibition of MDM2 with anti-MDM2 antisense oligonucleotide or Short Interference RNA targeting MDM2 significantly elevated p21 protein levels in PC3 cells (p53 null). In contrast, overexpression of MDM2 diminished the p21 level in the same cells by shortening the p21 half-life, an effect reversed by MDM2 antisense inhibition. MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein. In summary, we provide evidence supporting a physical interaction between MDM2 and p21. We also demonstrate that, by reducing p21 protein stability via proteasome-mediated degradation, MDM2 functions as a negative regulator of p21, an effect independent of both p53 and ubiquitination.
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PMID:MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. 1476 77

The 14-3-3sigma is a negative regulator of the cell cycle, which is induced by p53 in response to DNA damage. It has been characterized as an epithelium-specific marker and down-regulation of the protein has been shown in breast cancers, suggesting its tumor-suppressive activity in epithelial cells. Here we demonstrate that 14-3-3sigma protein is down-regulated in human prostate cancer cell lines, LNCaP, PC3, and DU145 compared with normal prostate epithelial cells. Immunohistochemical analysis of primary prostate cells shows that the expression of 14-3-3sigma protein is epithelial cell-specific. Among prostate pathological specimens, > 95% of benign hyperplasia samples show significant and diffuse immunostaining of 14-3-3sigma in the cytoplasm whereas < 20% of carcinoma samples show positive staining. In terms of mechanisms for the down-regulation of 14-3-3sigma in prostate cancer cells, hypermethylation of the gene promoter plays a causal role in LNCaP cells as 14-3-3sigma mRNA level was elevated by 5-aza-2'-deoxycytidine demethylating treatment. Intriguingly, the proteasome-mediated proteolysis is responsible for 14-3-3sigma reduction in DU145 and PC3 cells, as 14-3-3sigma protein expression was increased by treatment with a proteasome inhibitor MG132. Furthermore, tumor necrosis factor-related apoptosis-inducing ligand enhances 14-3-3sigma gene and protein expression in DU145 and PC3 cells. These data suggest that 14-3-3sigma expression is down-regulated during the neoplastic transition of prostate epithelial cells.
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PMID:14-3-3sigma is down-regulated in human prostate cancer. 1518 53

Exposure of cells to ionizing radiation slows the rate of degradation of substrates through the proteasome. Because the 26S proteasome degrades most short-lived cellular proteins, changes in its activity might significantly, and selectively, alter the life span of many signaling proteins and play a role in promoting the biological consequences of radiation exposure, such as cell cycle arrest, DNA repair, and apoptosis. Experiments were therefore undertaken to identify the radiation target that is associated with the proteasome. Regardless of whether they were irradiated before or after extraction and purification from human prostate cancer PC3 cells, 26S proteasomes remained intact but showed a rapid 30% to 50% dose-independent decrease in their three major enzymatic activities following exposure to 1 to 20 Gy. There was no effect on 20S proteasomes, suggesting that the radiation-sensitive target is located in the 19S cap of the 26S proteasome, rather than in the enzymatically active core. Because the base of the 19S cap contains an ATPase ring that mediates substrate unfolding, pore opening, and translocation of substrates into the catalytic chamber, we examined whether the ATPase activity of purified 26S proteasomes was affected. In fact, in vitro irradiation of proteasomes enhanced their ATPase activity. Furthermore, pretreatment with low concentrations of the free radical scavenger tempol was able to prevent both the radiation-induced decrease in proteolytic activity and the increase in ATP utilization, indicating that free radicals are mediators of these radiation-induced phenomena. Finally, we have shown that cell irradiation results in the accumulation of proteasome substrates: polyubiquitinated proteins and ornithine decarboxylase, indicating that the observed decrease in proteasome function is physiologically relevant.
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PMID:Proteasome structures affected by ionizing radiation. 1604 49

The proteasome-mediated protein degradation is critical for regulation of a variety of cellular processes, including cell cycle, cell death, differentiation and immune response. Proteasome inhibitors have recently been shown to be potent anti-cancer agents against a variety of cancer cells. Our study demonstrated that proteasome inhibitor MG132 (carbobenzoxy-L-leucyle-L-leucyl-L-leucinal) was a potent death-inducing agent for PC3 prostate cancer cells. MG132-induced cell death was partially inhibited by pan-caspase inhibitor zAVD-fmk and translational inhibitor cycloheximide. To understand the signaling pathways of proteasome inhibitor-induced cell death, we performed gene profiling study using Affymetrix human DNA microarrays to identify the genes whose expression was affected by proteasome inhibitor MG132 in PC3 cells. The genes with more than threefold increased expression induced by MG132 were functionally categorized into the following groups: heat shock and chaperone proteins, ubiquitination and protein degradation, transcription/translation factors, cell death and cell cycle arrest, signaling molecules and enzymes, and secreted cytokines. Among them, heat shock proteins and anti-oxidant enzymes may promote cell survival, while pro-death proteins such as GADD45B and STK17a may promote cell death. Interestingly, expression of a few autophagic genes was elevated by MG132 treatment. Furthermore, autophagy inhibitor 3-methyladenine partially inhibited MG132-induced cell death, indicating that autophagic cell death may contribute to MG132-induced cell death. Taken together, our results demonstrated that proteasome inhibition elicits activation of multiple signaling pathways in prostate cancer cells.
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PMID:Proteasome inhibition induces both pro- and anti-cell death pathways in prostate cancer cells. 1641 76

The purpose of this study is to evaluate the utility of MG-132, a broad spectrum proteasome inhibitor, to selectively enhance radiation sensitivity in prostate cancer without affecting normal surrounding urothelial tissue. PC3 prostate cancer cells and normal URO-tsa bladder epithelial cells were treated with or without MG-132 and exposed to 0, 2, 4, or 6 Gy radiation. Cell viability and clonogenic survival assays were performed, and nuclear factor kappa-B (NF-kappaB) activity was evaluated with electrophoretic mobility shift assay (EMSA). MG-132 was associated with decreased cell viability (between 24% and 33%) and clonogenic survival (between 71% and 88%) alone and in combination with radiation in PC3 cells. MG-132 had no effect on cell viability or clonogenic survival following radiation in URO-tsa cells. Constitutive and radiation-induced NF-kappaB binding activity was higher in PC3 cells compared with URO-tsa cells. Furthermore, MG-132 at concentrations associated with reductions in cell viability and clongenic survival inhibited NF-kappaB binding activity in PC3 cells with no effect in URO-tsa cells. These results provide strong evidence that proteasome inhibition and concomitant NF-kappaB inhibition can be used to selectively enhance tumor radiation sensitivity in prostate cancer without affecting normal surrounding bladder tissue.
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PMID:Selectively enhanced radiation sensitivity in prostate cancer cells associated with proteasome inhibition. 1659 99

Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small l-amino acids were used at P2, where d-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.
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PMID:Optimization of subsite binding to the beta5 subunit of the human 20S proteasome using vinyl sulfones and 2-keto-1,3,4-oxadiazoles: syntheses and cellular properties of potent, selective proteasome inhibitors. 1668 37

There has been intense investigation regarding the interaction between the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and p53 tumor suppressors. p53 has been shown to up-regulate PTEN expression as a transcriptional activator. However, clinical observations by immunohistochemistry studies indicate that significant increases in p53 protein levels coexist with reduced or absent expression of PTEN protein in a variety of neoplasias. In this study, we propose a mechanism that begins to explain how p53 can both up-regulate and down-regulate PTEN. We have found that PTEN protein is down-regulated under proteasome dysfunction induced by proteasome inhibitor MG132 in both human lymphoblast cells and MCF7 cells. The reduction of PTEN is coincident with elevated p53 protein levels and the association between PTEN and p53 but independent of its phosphatase activities. Quantitative reverse transcription-PCR indicates that proteasome inhibition does not reduce PTEN message levels but affects PTEN protein stability. The p53 inhibitor, pifithrin-alpha, is able to attenuate the effect of proteasome inhibition. Using ectopic expression studies in p53-null mouse embryonic fibroblasts and p53/PTEN-null PC3 cells, we show that PTEN is more stable in p53-null cells compared with p53-expressing cells. Inhibition of caspases, the downstream targets of p53, particularly caspase-3, can partially restore the stability of PTEN. This study provides the first evidence that p53 is able to down-regulate PTEN protein stability in stressed cells. Our study sheds some light on the mechanisms that regulate PTEN protein stability, which is important to fully elucidate to comprehend the broad neoplastic manifestations of Cowden syndrome/Bannayan-Riley-Ruvalcaba and sporadic cancers.
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PMID:p53 down-regulates phosphatase and tensin homologue deleted on chromosome 10 protein stability partially through caspase-mediated degradation in cells with proteasome dysfunction. 1677 87


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