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)

Rituximab (IDEC-C2B8, Mabthera(R)) is a chimeric (human-mouse) monoclonal antibody (MoAb) against the B-cell specific CD20-antigen. It has been used for the clinical treatment of non-Hodgkin's lymphomas, but variable clinical results suggest that some lymphoma cells remain resistant. In the present study we have evaluated the relative efficiencies of humoral and cell-mediated effector mechanisms complement-dependent cytotoxicity (CDC), antibody-(ADCC), complement-(CDCC) dependent cellular cytotoxicity and apoptosis on lymphoma cell killing by rituximab. Rituximab activated the cytolytic complement (C) cascade and induced a strong CDC, but the rituximab-triggered ADCC and CDCC were relatively ineffective. The CDC was strongly enhanced by antibodies against the C inhibitor CD59 (protectin). Neutralization of CD55 (DAF) and CD46 (MCP) had a similar but weaker effect. Rituximab also induced apoptosis but in a cell line-dependent fashion. The results strongly emphasize the role of direct CDC as the major, fast and efficient effector mechanism of rituximab. In the immunotherapeutic treatment of B-cell lymphomas, it is important to consider the role of C-regulatory proteins as an escape mechanism of the malignant cells. Our results suggest that the effect of rituximab therapy could be enhanced by combining it with neutralization of CD59.
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PMID:Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. 1084 76

Prompted by previous observations which suggested that the release of polymannose oligosaccharides shortly after the cotranslational N-glycosylation of proteins is a function of the ER-associated quality control system (Moore and Spiro (1994) J. Biol. Chem., 269, 12715-12721), we evaluated the effect which proteasome inhibitors have on the appearance of these free saccharide components. Employing as a model system castanospermine-treated BW5147 mouse T-lymphoma cells in which accelerated degradation of the T-cell receptor (TCR) alpha subunit takes place (Kearse et al. (1994) EMBO J., 13, 3678-3686), we noted that both lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, but not leupeptin, brought about a rapid and substantial reduction in the release of free polymannose oligosaccharides into the cytosol during pulse-chase studies, while the oligosaccharides in the intravesicular compartment remained unchanged, as measured by streptolysin O permeabilization. This inhibition was furthermore selective in that it affected solely the components terminating in a single N-acetylglucosamine residue (OS-GlcNAc(1)) and not the oligosaccharides terminating in a di-N-acetylchitobiose sequence (OS-GlcNAc(2)), which reside primarily in the intravesicular compartment. Despite the quantitative effect of the proteasome inhibitors on the cytosolic oligosaccharides, the molar distribution of the triglucosyl OS-GlcNAc(1) species was unaffected. The decrease in cytosolic oligosaccharides brought about by proteasome inhibition was reflected in a pronounced increase in the stability of the TCRalpha subunit. Our findings suggest that the N-deglycosylation and proteasome mediated degradation are coupled events. On the basis of our data and those of others we propose that the quality control mechanism involves proteasomes associated with the cytosolic side of the endoplasmic reticulum acting in concert with a membrane situated N-glycanase. Such a complex by removing the carbohydrate units could facilitate the retrograde ER to cytosol translocation of glycoproteins.
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PMID:Effect of proteasome inhibitors on the release into the cytosol of free polymannose oligosaccharides from glycoproteins. 1091 Sep 76

The ubiquitin-proteasome-dependent proteolytic system has been reported to regulate apoptotic cell death in many experimental cell models. We recently found that B-CLL (chronic lymphocytic leukemia) lymphocytes are hypersensitive to apoptotic death activation through specific inhibition of proteasome function by lactacystin. Lactacystin efficiently activates apoptotic death process in B-CLL lymphocytes at doses at which no apoptotic effect can be observed in normal human lymphocytes in which 10-fold higher doses of lactacystin are required to weakly induce apoptosis. This hypersensitivity of B-cell CLL may be a result of an altered ubiquitin pathway and proteasomal proteolysis in these malignant cells, and this alteration could be specific for this malignancy. Together with other published works, these results suggest that lactacystin, though not per se a discriminatory inhibitor of the ubiquitinated protein processing/degradation, can nonetheless be discriminatory in the apoptotic cell response between B-CLL and normal lymphocytes: the property that promises efficacy in clinical trials of B-cell CLL. This hypothesis is documented by the fact that lymphocytes from patients in complete remission become resistant to lactacystin-induced apoptosis as normal lymphocytes do.
Leuk Lymphoma 2000 Aug
PMID:Ubiquitin-proteasome system and increased sensitivity of B-CLL lymphocytes to apoptotic death activation. 1095 70

Release of calcium from the endoplasmic reticulum (ER) signals an increase in transcription of both the early response gene, c-fos, and the late response gene, grp78. We have used thapsigargin (TG), an ER calcium-ATPase pump inhibitor that induces calcium release from the ER, to investigate the possible involvement of c-Fos, a component of the AP-1 transcription factor, in grp78 induction. Two cell lines with markedly different responses to TG treatment were employed: the WEHI7.2 mouse lymphoma line in which TG fails to induce grp78, and the MDA-MB-468 mammary epithelial line in which TG induces grp78. In WEHI7.2 cells, TG-induced calcium release triggers a rapid increase in c-fos mRNA, but the level of c-Fos protein decreases due to degradation by the multicatalytic proteasome. C-FosdeltaC, a proteasome resistant c-Fos mutant with AP-1 activity similar to that of wild type c-Fos, restores grp78 induction in WEHI7.2 cells, detected by both Northern hybridization and a grp78 promoter-luciferase reporter assay. In MDA-MB-468 cells, TG-mediated calcium release induces a sustained elevation of c-Fos protein that precedes grp78 induction. A region of the grp78 promoter containing both ERSE and CORE regions, but missing TRE and CRE regions, is sufficient to mediate induction of reporter luciferase activity. Induction of this reporter was blocked by A-Fos, a dominant negative inhibitor of c-Fos. Also, the induction of grp78-luciferase reporter activity was inhibited by c-fos antisense mRNA. In summary, the findings indicate that c-Fos is involved in signaling grp78 induction following TG treatment, and that grp78 induction is inhibited by proteasome-mediated c-Fos degradation.
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PMID:Involvement of c-Fos in signaling grp78 induction following ER calcium release. 1112 25

Some tumor cells have deficits in class I MHC antigen processing, suggesting that T cells exert selective pressure on tumor cells. Previous studies have not revealed increased tumor incidence in mice with deficits in T-cell immunity, including mice lacking TAP1 (a subunit of the transporter for antigen presentation) or LMP2 (a regulated subunit of the 20S proteasome). The incidence of spontaneous tumors in these mice, however, is too low to assess differences in host resistance to tumors. To increase tumor incidence and better assess the role of systemic expression of TAP1 and LMP2 in responses to tumors, TAP1-/- and LMP2-/- mice were bred with p53-/- mice to create TAP1-/-p53-/- and LMP2-/-p53-/- double knockout mice. Lymphomas and sarcomas (malignant fibrous histiocytoma and angiosarcoma) occurred with high incidence in all p53-deficient populations. Tumor incidence and death rate were similar in TAP1-/-p53-/- mice and closely matched control TAP1+/+p53-/- mice. Tumor incidence and death rate were slightly accelerated in LMP2-/-p53-/- mice relative to control LMP2+/+p53-/- mice, but the biological significance of this difference was unclear. The relative incidence of lymphomas vs. sarcomas was not significantly altered by variation in TAP1 or LMP2. In conclusion, systemic absence of TAP1 did not alter tumor incidence, while absence of LMP2 was associated with only a slight acceleration of tumor incidence of uncertain significance. These observations are consistent with other evidence that normal T-cell responses do not effectively limit tumorigenesis. Even though T cells can attack some tumor cells, the ability of tumors to alter their immunogenicity and evade T-cell surveillance may render the native immune system ineffective at providing a rate-limiting barrier to tumorigenesis and preventing cancer.
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PMID:Systemic deficits in transporter for antigen presentation (TAP)-1 or proteasome subunit LMP2 have little or no effect on tumor incidence. 1116 61

To understand the molecular mechanisms involved in preleukemia, the suppression subtractive hybridization method was used in a murine radiation-induced thymic lymphoma model. Seventeen mRNAs overexpressed in preleukemic thymuses were identified: mouse laminin binding protein (p40/37LBP), E25 protein, Rattus norvegicus clone BB.1.4.1, profilin, poly(A) binding protein (PABP), mouse high mobility group protein 1, topoisomerase I, clusterin, proteasome RC1 subunit, rat prostatein C3 and C1 subunits; two ESTs and four unknown genes. The overexpression of PABP, clusterin, profilin, and the p40/37LBP mRNAs was confirmed in preleukemic thymuses and can be related to some cellular events observed during the preleukemic period, i.e., alterations of cell cycle and apoptosis properties. The p40/37LBP and 67-kDa laminin receptor proteins were upregulated during the preleukemic period. The data suggest that additional studies on p40/37LBP and 67-kDa laminin receptor regulation are required to evaluate their potential role in the lymphoma prevention by TNF-alpha and IFN-gamma.
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PMID:Genetic imbalances in preleukemic thymuses. 1132 60

The cyclin-dependent kinase inhibitor p27KIP1 plays a key role in controlling cell proliferation. Here we show that p27KIP1 is commonly down-regulated in B-cells immortalized by Epstein-Barr virus (EBV) (lymphoblastoid cell lines, LCLs). The significance of this event for the immortal phenotype of LCLs is implied by a requirement for active cdk2-containing complexes for continued proliferation, and by the ability of the residual p27KIP1 to associate with cdk2. The mechanism of p27KIP1 attenuation is post-translational, but inhibitor studies reveal that the mechanism does not rely heavily on the proteasome. Instead we find that LCLs contain an activity that cleaves a caspase recognition site present in p27KIP1 (DPSD139). The activity is not associated with apoptosis and closely resembles a proliferation-associated caspase activity we previously described in the EBV-negative B-lymphoma-derived cell line BJAB. Importantly, proliferating LCLs contain a p27KIP1 product that is consistent with cleavage at this site. Inhibition of caspase(s) in vivo modulates p27KIP1 expression and strongly inhibits proliferation of IB4 cells. This inhibitor profile is identical to that displayed by the DPSD-directed caspase present in BJAB cells, suggesting that the caspase may fulfil a general role in controlling p27KIP1 expression in immortal lymphoid cell lines. Thus, apoptosis-independent cleavage appears to contribute to the maintenance of the low basal levels of p27KIP1 in B-cells immortalized by EBV.
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PMID:Regulation of p27KIP1 in Epstein-Barr virus-immortalized lymphoblastoid cell lines involves non-apoptotic caspase cleavage. 1171 84

The ubiquitin system regulates diverse biological processes such as DNA replication and repair, biogenesis of ribosome, peroxisome and nucleosome, cell cycle, stress response and signal transduction pathways. Thus, the reported role of the ubiquitin system in apoptotic death control as well the alteration of its control in carcinogenesis should come as no surprise. Indeed, we and other groups have reported that the ubiquitin system is involved in apoptotic cell death of normal human lymphocytes and that this control is altered in B lymphocytes derived from chronic lymphocytic leukemia patients (B-CLL), rendering these malignant cells hypersensitive to specific inhibition of protein degradation/processing through proteasomal function. This approach recently allowed us to demonstrate that the stability of the tumor suppressor and pro-apoptotic protein p53 is differentially regulated in B-CLL versus normal lymphocytes and that this difference might at least partly explain the impaired response of B-CLL lymphocytes to apoptotic death activation. These results strongly suggest an imbalance in p53 regulation in B-CLL cells that leads to a variable response to DNA damage and constitutively expressed chromosomal instability. The question we and others would like to address is whether this alteration, or more likely a subset of alterations of the ubiquitin-proteasome pathway, is specific to B-CLL malignancy or if it is a hallmark of cancer cells in general. In either case, a better understanding of the ubiquitin-dependent control of apoptosis should pave the way towards a methodological approach for in vitro development of discriminating treatments which may be of potential usefulness in clinical trials of B-CLL.
Leuk Lymphoma
PMID:Chromosomal DNA and p53 stability, ubiquitin system and apoptosis in B-CLL lymphocytes. 1191 98

In patients (pts) with non-Hodgkin's lymphoma (NHL) under 25 years, treatment with MCP-842 protocol, a short duration intense protocol, yields worse survival in pts with lymphoblastic lymphoma (LL) compared to other high grade lymphomas. In order to identify both favourable and unfavourable subgroups in pts with T-cell LL (T-LL) with respect to relapse free survival following treatment with MCP-842 protocol, we analysed the expression of p53 and bcl-2 proteins in 22 pts with T-LL treated at the Tata Memorial Hospital, Mumbai by immunohistochemistry. p53 protein overexpression was noted in 59% cases and bcl-2 overexpression was noted in 29.4% cases. p53 expression correlated with a higher rate of relapse (p = 0.03; RR 7.9). The 5-year relapse free survival (RFS) was better in p53 negative patients compared to positive patients (70 vs 38%) (log-rank sigma = 0.04). In conclusion, in this study, overexpression of p53 protein was common in patients with T-LL. T-LL pts negative for p53 are likely to benefit from the short intense protocol--MCL-842. Bcl-2 protein overexpression was not a prognostic factor in these patients.
Leuk Lymphoma 2002 Feb
PMID:Expression of P53 and bcl-2 proteins in T-cell lymphoblastic lymphoma: prognostic implications. 1199 65

Precise control of the level of c-Myc protein is important to normal cellular homeostasis, and this is accomplished in part by degradation through the ubiquitin-proteasome pathway. The calpains are a family of calcium-dependent proteases that play important roles in proteolysis of some proteins, and their possible participation in degradation of intracellular c-Myc was therefore investigated. Activation of calpain with the cell-permeable calcium ionophore A23187 in Rat1a-myc or ts85 cells in culture induced rapid cleavage of c-Myc. This degradation was both calpain- and calcium-dependent since it was inhibited by preincubation with either the calpain-inhibitory peptide calpeptin or the calcium-chelating agent EGTA. A23187-induced c-Myc cleavage occurred in a time-dependent manner comparable to that of FAK, a known calpain substrate, and while calpeptin was able to significantly protect c-Myc from degradation, inhibitors of the proteasome or caspase proteases could not. Exposure of Rat1a-myc or ts85 cells in culture to calpeptin, or to the thiol-protease inhibitor E64d, resulted in the accumulation of c-Myc protein without an impact on ubiquitin-protein conjugates. Using an in vitro assay, calpain-mediated degradation occurred rapidly with wild-type c-Myc as the substrate, but was significantly prolonged in some c-Myc mutants with increased transforming activity derived from lymphoma patients. Those mutants with a prolonged half-life in vitro were also more resistant to A23187-induced cleavage in intact cells. These studies support a role for calpain in the control of c-Myc levels in vivo, and suggest that mutations impacting on sensitivity to calpain may contribute to c-Myc-mediated tumorigenesis.
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PMID:Evidence for involvement of calpain in c-Myc proteolysis in vivo. 1205 25


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