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)

The ubiquitin-proteasome pathway is the principal mechanism for the degradation of short-lived proteins in eukaryotic cells. We demonstrated that treatment of THP-1 human monocytic leukemia cells with Z-LLL-CHO, a reversible proteasome inhibitor, induced cell death through an apoptotic pathway. Apoptosis in THP-1 cells induced by Z-LLL-CHO involved a cytochrome c-dependent pathway, which included the release of mitochondrial cytochrome c, activation of caspase-9 and -3, and cleavage of Bcl-2 into a shortened 22-kDa fragment. Induction of apoptosis by protease inhibitor also was detected in U937 and TF-1 leukemia cell lines and cells obtained from acute myelogenous leukemia patients but not in normal human blood monocytes. Treatment of human blood monocytes with Z-LLL-CHO did not induce apoptosis or Bcl-2 cleavage in these cells that rarely proliferate. Interestingly, when THP-1 cells were induced to undergo monocytic differentiation by bryostatin 1, a naturally occurring protein kinase C activator, they were no longer susceptible to apoptosis induced by Z-LLL-CHO. Bryostatin 1-induced differentiation of THP-1 cells was associated with growth arrest, acquisition of adherent capacity, and expression of membrane markers characteristic of blood monocytes. Likewise, differentiated THP-1 cells were refractory to Z-LLL-CHO-induced cytochrome c release, caspase activation, and Bcl-2 cleavage. Resistance to Z-LLL-CHO-induced apoptosis in differentiated THP-1 cells was not due to cell cycle arrest. These findings show that the action of proteasome inhibitors is mediated primarily through a cytochrome c-dependent pathway and induces apoptosis in leukemic cells that are not differentiated.
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PMID:Human THP-1 monocytic leukemic cells induced to undergo monocytic differentiation by bryostatin 1 are refractory to proteasome inhibitor-induced apoptosis. 1096 81

Biochemical and genetic analysis of apoptosis has determined that intracellular proteases are key effectors of cell death pathways. In particular, early studies have pointed to the primacy of caspase proteases as mediators of execution. More recently, however, evidence has accumulated that noncaspases, including cathepsins, calpains, granzymes, and the proteasome complex, also have roles in mediating and promoting cell death. An important goal is to understand the importance of distinct noncaspases in various forms of apoptosis, and to determine whether pathways mediated by noncaspase proteases intersect with those mediated by caspases. In this review the roles of noncaspase proteases in the biochemistry of apoptosis will be discussed.
Leukemia 2000 Sep
PMID:Noncaspase proteases in apoptosis. 1099 18

Treatment of different human leukemia cell variants with the anthracycline adriamycin was associated with a rapid activation of the proteasome. Thus, proliferating U937, TUR, and retrodifferentiated U937 cells exhibited a 4.3-fold, 5.8-fold, and 4.3-fold proteasome activation within 15 minutes after adriamycin treatment, respectively. In contrast, little if any proteasome activation was detectable in a growth-arrested differentiated U937 population following adriamycin treatment. Further analysis of this mechanism revealed a significant reduction of adriamycin-induced proteasome activity after inhibition of poly(ADP-ribose) polymerase (PARP) by 3-aminobenzamide (3-ABA) in the proliferating leukemic cell types. These findings suggested that PARP is involved in the regulation of drug-induced proteasome activation. Indeed, anti-PARP immunoprecipitation experiments of adriamycin-treated cells revealed increasing levels of coprecipitated, enzymatically active proteasome particularly in the proliferating cell variants in contrast to the differentiated U937 cells, with a maximum after 15 minutes, and sensitivity to PARP inhibition by 3-ABA. The specific role of the PARP was investigated in U937 and TUR cell clones stably transfected with a constitutively active antisense PARP (asPARP) vector. Thus, asPARP-TUR cells developed a 25-fold increased sensitivity to adriamycin treatment. Furthermore, we investigated leukemic blasts isolated from acute myelogenous leukemia patients and obtained a similarly enhanced proteasome activity after adriamycin treatment, which was dependent on the PARP and thus could be coprecipitated with anti-PARP antibodies. Transient transfection of leukemic blasts with the asPARP vector significantly reduced the adriamycin-induced proteasome activation. These data suggest that the PARP-associated nuclear proteasome activation represents a potential target within chemotherapeutic defense mechanisms developed by leukemia cells.
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PMID:Regulation of the nuclear proteasome activity in myelomonocytic human leukemia cells after adriamycin treatment. 1131 78

The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.
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PMID:The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. 1131 18

Human T-cell leukemia virus type 1 (HTLV-1) establishes a persistent infection in the host despite a vigorous virus-specific immune response. Here we demonstrate that an HTLV-1-encoded protein, p12(I), resides in the endoplasmic reticulum (ER) and Golgi and physically binds to the free human major histocompatibility complex class I heavy chains (MHC-I-Hc) encoded by the HLA-A2, -B7, and -Cw4 alleles. As a result of this interaction, the newly synthesized MHC-I-Hc fails to associate with beta(2)-microglobulin and is retrotranslocated to the cytosol, where it is degraded by the proteasome complex. Targeting of the free MHC-I-Hc, and not the MHC-I-Hc-beta(2)-microglobulin complex, by p12(I) represents a novel mechanism of viral interference and disrupts the intracellular trafficking of MHC-I, which results in a significant decrease in surface levels of MHC-I on human T-cells. These findings suggest that the interaction of p12(I) with MHC-1-Hc may interfere with antigen presentation in vivo and facilitate escape of HTLV-1-infected cells from immune recognition.
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PMID:Free major histocompatibility complex class I heavy chain is preferentially targeted for degradation by human T-cell leukemia/lymphotropic virus type 1 p12(I) protein. 1139 Jun 10

Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of B-CLL cells. Activation of B-CLL lysates with dATP results in the formation of an approximately 700 kDa caspase-activating apoptosome complex containing Apaf-1. We describe for the first time the formation of a similar approximately 700 kDa caspase-activating apoptosome complex in B-CLL cells induced to undergo apoptosis by proteasome inhibitors.
Leukemia 2001 Sep
PMID:Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. 1151 99

Lithium affects several enzymatic activities, however, the molecular mechanisms of lithium actions are not fully understood. We previously showed that LiCl interacts synergistically with all-trans-retinoic acid to promote terminal differentiation of WEHI-3B D(+) cells, a phenomenon accompanied by the recovery of the retinoid-induced loss of retinoic acid receptor alpha protein pools. Here, we demonstrate the effects of LiCl on proteasome-dependent degradation of retinoic acid receptor alpha proteins. LiCl alone, or in combination with all-trans-retinoic acid, increased cellular levels of ubiquitinated retinoic acid receptor alpha and markedly reduced chymotryptic-like activity of WEHI-3B D(+) 20 S and 26 S proteasome enzymes. Neither KCl nor all-trans-retinoic acid affected enzyme activity, whereas NaCl produced a modest reduction at relatively high concentrations. In addition, LiCl inhibited 20 S proteasome chymotryptic-like activity from rabbits but had no effect on tryptic-like activity of the 26 S proteasome. This effect has significant consequences in stabilizing the retinoic acid receptor alpha protein levels that are necessary to promote continued differentiation of leukemia cells in response to all-trans-retinoic acid. In support of this concept, combination of proteasome inhibitors beta-clastolactacystin or benzyloxycarbonyl-Leu-Leu-Phe with all-trans-retinoic acid increased differentiation of WEHI-3B D(+) cells in a manner that was analogous to the combination of LiCl and all-trans-retinoic acid.
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PMID:Inhibition of 20 S and 26 S proteasome activity by lithium chloride: impact on the differentiation of leukemia cells by all-trans retinoic acid. 1155 54

Moloney murine leukemia virus (MoMuLV)-ts1-mediated neuronal degeneration in mice is likely due to loss of glial support and release of inflammatory cytokines and neurotoxins from surrounding ts1-infected glial cells including astrocytes. NF-kappaB is a transcription factor that participates in the transcriptional activation of a variety of immune and inflammatory genes. We investigated whether ts1 activates NF-kappaB in astrocytes and examined the mechanism(s) responsible for the activation of NF-kappaB by ts1 infection in vitro. Here we present evidence that ts1 infection of astrocytes in vitro activates NF-kappaB by enhanced proteolysis of the NF-kappaB inhibitors, IkappaBalpha and IkappaBbeta. In in vitro studies using protease inhibitors, IkappaBalpha proteolysis in ts1-infected astrocytes was significantly blocked by a specific calpain inhibitor calpeptin but not by MG-132, a specific proteasome inhibitor, whereas rapid IkappaBbeta proteolysis was blocked by MG-132. Furthermore, treatment with MG-132 increased levels of multiubiquitinated IkappaBbeta protein in ts1-infected astrocytes. These results indicate that the calpain proteolysis is a major mechanism of IkappaBalpha proteolysis in ts1-infected astrocytes. Additionally, ts1 infection of astrocytes in vitro increased expression of inducible nitric oxide synthase (iNOS), a NF-kappaB-dependent gene product. Our results suggest that NF-kappaB activation in ts1-infected astrocytes is mediated by enhanced proteolysis of IkappaBalpha and IkappaBbeta through two different proteolytic pathways, the calpain and ubiquitin-proteasome pathways, resulting in increased expression of iNOS, a NF-kappaB-dependent gene.
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PMID:Enhanced proteolysis of IkappaBalpha and IkappaBbeta proteins in astrocytes by Moloney murine leukemia virus (MoMuLV)-ts1 infection: a potential mechanism of NF-kappaB activation. 1158 19

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates the HTLV-1 long terminal repeat and key regulatory proteins involved in inflammation, activation, and proliferation and may induce cell transformation. Tax is also the immunodominant target antigen for cytotoxic T cells in HTLV-1 infection. We found that Tax bound to assembled nuclear proteasomes, but Tax could not be detected in the cytoplasm. Confocal microscopy revealed a partial colocalization of Tax with nuclear proteasomes. As Tax translocated into the nucleus very quickly after synthesis, this process probably takes place prior to and independent of proteasome association. Tax mutants revealed that both the Tax N and C termini play a role in proteasome binding. We also found that proteasomes from Tax-transfected cells had enhanced proteolytic activity on prototypic peptide substrates. This effect was not due to the induction of the LMP2 and LMP7 proteasome subunits. Furthermore, Tax appeared to be a long-lived protein, with a half-life of around 15 h. These data suggest that the association of Tax with the proteasome and the enhanced proteolytic activity do not target Tax for rapid degradation and may not determine its immunodominance.
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PMID:Human T-cell leukemia virus type 1 Tax protein binds to assembled nuclear proteasomes and enhances their proteolytic activity. 1160 50

The leukemias are complex diseases with a wide range of clinical, morphologic, biologic, molecular, and clinical features and a consequent array of possible responses to any given intervention. Although progress has been made in the management of the leukemias, most patients who fail to respond to front-line therapies or who relapse after an initial response die from progressive disease. The balance between efficacy and toxicity of traditional cytotoxic therapies is increasingly unacceptable. As a consequence, the search for therapeutic advances is more focused on affecting the critical steps involved in the development, propagation, and mutation of malignant clones. This article briefly reviews current data on some agents being developed for the treatment of patients with leukemia, with an emphasis on modulators of angiogenesis, inhibitors of the ubiquitin-proteasome pathway, novel nucleoside analogues, and gene hypomethylation agents.
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PMID:Novel agents for the therapy of acute leukemia. 1179 Sep 73


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