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)

An L1210 cell line (Y8) selected for resistance to deoxyadenosine does not express p53 mRNA or protein but expresses WAF1/p21 even under basal conditions. The Y8 cell line had been previously shown to have an increased apoptotic response to a variety of agents that included DNA damaging agents, kinase inhibitors and drugs directed at NFkappa B activation. In this study we show that lactacystin (LC, an inhibitor of proteasome activity) in combination with parthenolide (PA) caused a synergistic increase in the apoptotic fraction of the Y8 cells. LC (2.5 microM) alone and PA (5.0 microM) caused less than 20% of the Y8 cells to undergo apoptosis. However, the combination of LC (2.5 microM) plus PA (5.0 microM) caused 60% of the Y8 cells to undergo apoptosis. The combination of drugs had no effects on the parental wild-type L1210 cells. Pretreatment of the intact Y8 cells with the caspase-3 inhibitor, Ac-DEVD-CHO, resulted in a marked decrease in the apoptosis caused by the LC plus PA combination. Cell-free extracts prepared from the LC plus PA combination-treated cells had activated caspase activities in the caspase cascade: caspase-3 >> caspase-8 > caspase-6 and caspase-10. These results suggest that there are interacting pathways involving aspects of NFkappa B activation and proteasome activity that could be exploited in therapy directed at p53-deficient tumor cells that would lead to caspase-3 activation and apoptosis bypassing the p53-dependent chemotherapy insensitivity.
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PMID:Lactacystin, a proteasome inhibitor, potentiates the apoptotic effect of parthenolide, an inhibitor of NFkappaB activation, on drug-resistant mouse leukemia L1210 cells. 1255 98

We have isolated Ubp41, a ubiquitin-specific protease, in a screen for proapoptoticgenes. We found that overexpression of Ubp41 is sufficient to elicit all features of apoptosis in human cells. In contrast, an enzymatically defective UBP41 mutant and homologous ubiquitin-processing protease family members did not significantly induce cell death. Overexpression of Ubp41 resulted in a strong deubiquitination of a broad range of proteins, but surprisingly did not lead to a stabilization of protein substrates known to be regulated by the ubiquitin-proteasome system such as the cell cycle factors p21 and p27. Hence, in contrast to the proteasome inhibitor MG132, Ubp41 overexpression did not arrest cells in G(2)/M. Rather, overexpression of hUbp41 seems to interfere with the ubiquitin-system and to cause the activation of apoptosis pathways by stabilizing specific substrates. Hence, for the first time we found that a member of the deubiquitinating enzymes has a direct proapoptotic activity additionally tightening the connection between apoptosis and the ubiquitin-proteasome system.
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PMID:UBP41 is a proapoptotic ubiquitin-specific protease. 1256 14

Our aim was to determine the molecular targets involved in the antiproliferative effects of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), in a normal murine mammary epithelial cell line, HC11. Among the early response genes analyzed, c-myc, junB, junD, c-jun, c-fos, fosB, fra, as well as max, mad1-4, sin3, only c-jun and fra-2 mRNAs were up-regulated after 1,25(OH)(2)D(3) exposure. Cyclin C was reduced and cyclin A2 and E were slightly enhanced; however, cyclins D1, D3, B1, B2, F, G1, G2, I and H, as well as TGF beta 1, TGF beta 3, T beta RI and T beta RII transcripts were not modulated by 1,25(OH)(2)D(3). Although p27(KIP1) protein content was unchanged, enhancement of p21(WAF1/CIP1) low basal levels in cell extracts and IGFBP-3 abundance on the culture medium was detected after 1,25(OH)(2)D(3) induction. Using differential display analysis, we identified eight down-modulated clones in exposed cells: 26S proteasome non-ATPase subunit Pad1, ubiquitin-conjugating enzyme Ube2i, extracellular proteinase inhibitor Expi or Wdnm1, cytochrome-c oxidase Cox7c, microtubule-associated protein-1 light chain-3 (Map1lc3), nascent-associated complex alpha Naca, transforming acidic coiled-coil Tacc3, stearoyl-CoA desaturase (Scd), keratin 6 alpha, and 1 up-regulated, fork head transcription factor Hfh-1L. Hence, the antiproliferative effect of 1,25(OH)(2)D(3) seems associated to enhancement of c-jun, Fra-2, IGFBP3 and p21(WAF1/CIP1). Decreased Pad1 and Ube2i might account for increased stability of cell cycle inhibitory proteins while reduced Wdnm1, Tacc3 and Scd might be secondary to accumulation of cells in G0/G1 phase.
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PMID:Molecular targets of 1,25(OH)2D3 in HC11 normal mouse mammary cell line. 1264 25

Ras promotes the accumulation of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (p21). Previous studies reported that acute Raf/MEK/ERK activation elevates p21 protein levels by increased transcription. However, we have found that p21 induction in Ras-transformed murine fibroblasts occurs principally by a post-translational mechanism. Chronic activation of the Raf/MEK/ERK pathway blocked proteasome-mediated p21 degradation, resulting in accumulation of p21 protein with an elevated half-life. The stabilization of p21 by Ras was accompanied by high levels of p21-associated cyclin D1 and, similarly to Ras, cyclin D1 was sufficient to inhibit the proteasome-mediated p21 degradation. Knock-down of cyclin D1 by RNA interference confirmed that Ras-induced p21 stabilization was dependent upon cyclin D1 expression. We show that p21 directly binds to the C8alpha subunit of the 20S proteasome complex and that by competing for binding, cyclin D1 inhibits p21 degradation by purified 20S complexes in vitro. Therefore, we propose that Ras stabilizes p21 by promoting the formation of p21-cyclin D1 complexes that prevent p21 association with, and subsequent degradation by, the 20S proteasome.
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PMID:Ras promotes p21(Waf1/Cip1) protein stability via a cyclin D1-imposed block in proteasome-mediated degradation. 1272 71

The proteasome plays a critical role in regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. Preclinical research has shown that through the prevention of IkappaB degradation, bortezomib may block chemotherapy-induced NF-kappaB activation and augment the apoptotic response to chemotherapeutic agents. Bortezomib also appeared to increase the stabilization of p21 and p27, as well as transcription factor p53. In preclinical models of breast, lung, pancreatic, and ovarian tumor types, bortezomib inhibited tumor growth and demonstrated anti-angiogenic properties. Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, such as irinotecan, gemcitabine, and docetaxel, suggesting its potential additive/syngeristic role in overcoming resistance to conventional chemotherapy. Preliminary data from early clinical trials suggest that bortezomib can be given at pharmacologically active doses in combination with standard doses of chemotherapy with manageable toxicities. Responses have been seen and no evidence of additive toxicity has been exhibited in combination agent trials.
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PMID:Clinical update: proteasome inhibitors in solid tumors. 1273 42

Human papillomavirus (HPV) E6 viral oncoprotein plays an important role during cervical carcinogenesis. This oncoprotein binds the tumor suppressor protein p53, leading to its degradation via the ubiquitin-proteasome pathway. Therefore, it is generally assumed that in HPV-positive cancer cells p53 function is completely abolished. Nevertheless, recent findings suggest that p53 activity can be recovered in cells expressing endogenous E6 protein. To investigate whether p53-dependent functions controlling genome integrity, cell proliferation, and apoptosis can be reactivated in cervical cancer cells, we examined the capacity of HeLa, INBL, CaSki, C33A, and ViBo cell lines to respond to neocarzinostatin (NCS), a natural product which induces single- and double-strand breaks in DNA. We found that NCS treatment inhibits cellular proliferation through G2 cell cycle arrest and apoptosis induction. This effect was preceded by nuclear accumulation of p53 protein and by an increase of p21 transcripts. Although apoptosis was blocked in ViBo cells (HPV-negative), nuclear accumulation of transcriptionally active p53 and inhibition of cell proliferation are observed after NCS treatment. These results suggest that HPV-positive cervical cancer cells are capable of responding efficiently to DNA damage provoked by NCS treatment through a p53-dependent pathway in spite of the presence of E6 protein.
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PMID:Neocarzinostatin induces an effective p53-dependent response in human papillomavirus-positive cervical cancer cells. 1275 Apr 35

The effects of proteolysis inhibitors on hydrogen peroxide (H(2)O(2))-induced apoptosis were examined in cultured human synovial cells of rheumatoid arthritis (RA) patients. RA synovial cells were resistant to apoptosis induced by H(2)O(2). In the presence of 100 microM N-acetyl-leucyl-leucyl-norleucinal (ALLN, known as calpain inhibitor 1 and also a proteasome inhibitor), but not N-acetyl-leucyl-leucyl-methioninal (ALLM), apoptotic cell death was elicited by 400 microM H(2)O(2) at a concentration that alone never induced cell death. ALLN induced the expression of tumor suppressor p53 protein and p21(WAF-1) protein, probably through inhibition of proteasome. H(2)O(2) further potentiated ALLN-induced p53 expression. H(2)O(2) appeared to activate c-Jun N-terminal kinase (JNK) as well as extracellular signal-regulated kinase (ERK) and AKT. After administration of H(2)O(2) and p53 induction by ALLN, we found that either one alone is insufficient to induce apoptosis of RA synovial cells but their combination synergistically does so. These results suggest that induction of p53 by ALLN may be potentially important for triggering H(2)O(2)-induced apoptosis processes in RA synovial cells.
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PMID:Synergistic induction of apoptosis of rheumatoid arthritis synovial cells by H(2)O(2) and N-acetyl-leucyl-leucyl-norleucinal. 1276 77

Proteasome activity is essential during cAMP-induced terminal differentiation of a murine neuroblastoma cell line (NBP2). However, the mechanisms through which proteasome affects NBP2 differentiation have not been characterized. We hypothesized that proteasome is required to implement the differentiation-mediated effects on cell cycle, and its partial inhibition during differentiation may have adverse consequences. Here we show that partial inhibition of proteasome during cAMP-induced differentiation of NBP2 cells causes apoptosis. Whereas differentiation induced growth arrest at G1 phase, partial proteasome inhibition during differentiation resulted in the accumulation of cells at G2M phase. Cell cycle data correlated with the level of cyclin-dependent kinase inhibitors p21WAF and p27Kip1, and cyclin A. While the level of p21 and p27 increased, the level of cyclin A decreased upon differentiation. In contrast, cells treated with proteasome inhibitor in the presence of cAMP-inducing agents showed increased levels of p21 and cyclin A early in the course of differentiation. However, the level of p21 and p27, but not cyclin A, decreased later during concomitant differentiation and partial proteasome inhibition when cells were undergoing apoptosis. Our data suggest that differentiation-mediated growth arrest is dependent on the temporal activity of cell cycle proteins. Partial inhibition of proteasome interferes with differentiation events partly by stabilizing cell cycle proteins and this triggers apoptosis. Thus, differentiating drugs combined with partial proteasome inhibition may impart higher therapeutic efficacy than differentiating agents alone for the treatment of neuroblastoma tumors.
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PMID:Concomitant differentiation and partial proteasome inhibition trigger apoptosis in neuroblastoma cells. 1281 50

Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM.
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PMID:NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. 1281 65

Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma subtype, characterized by overexpression of cyclin D1 as a consequence of the chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed. The present study investigated the effect of a specific proteasome inhibitor, lactacystin, on cell cycle progression and apoptosis in two lymphoma cell lines harbouring the t(11;14)(q13;q32) and additional cytogenetic alterations, including p53 mutation (NCEB) and p16 deletion (Granta 519). Granta cells were more susceptible to inhibition of the proteasome with respect to inhibition of proliferation and apoptosis induction. No changes were observed in the expression levels of the G1 regulatory molecules cyclin D1 and cdk4, but cell cycle arrest and apoptosis induction was accompanied by accumulation of the cdk inhibitor p21 in both cell lines. Increased p53 expression was only observed in Granta cells with wild-type p53. Cleavage of procaspase-3 and -9 was observed but cleavage of procaspase-8 was not involved in apoptosis induction. The proapoptotic effect of lactacystin was reversed by pretreatment with the pancaspase inhibitor zVAD.fmk. Lactacystin was also effective in inducing apoptosis in lymphoma cells from MCL patients. We conclude that inhibition of the proteasome might be a promising therapeutic approach for this incurable disease.
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PMID:Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells. 1284 95


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