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)

Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-kappaB activity by blocking proteasomal degradation of inhibitor of kappaBalpha (IkappaBalpha). Bortezomib inhibits inducible NF-kappaB activity; however, its impact on constitutive NF-kappaB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IkappaBalpha expression and triggered NF-kappaB activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-kappaB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IkappaBalpha down-regulation associated with NF-kappaB activation. Molecular mechanisms whereby bortezomib induced IkappaBalpha down-regulation were further examined. Bortezomib triggered phosphorylation of IkappaB kinase (IKKbeta) and its upstream receptor-interacting protein 2, whereas IKKbeta inhibitor MLN120B blocked bortezomib-induced IkappaBalpha down-regulation and NF-kappaB activation, indicating receptor-interacting protein 2/IKKbeta signaling plays crucial role in bortezomib-induced NF-kappaB activation. Moreover, IKKbeta inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-kappaB activity in MM cells.
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PMID:Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. 1964 92

The Carma1-Bcl10-Malt1 (CBM) complex connects T-cell receptor (TCR) signalling to the canonical IkappaB kinase (IKK)/NF (nuclear factor)-kappaB pathway. Earlier studies have indicated that the COP9 signalosome (CSN), a pleiotropic regulator of the ubiquitin/26S proteasome system, controls antigen responses in T cells. The CSN is required for the degradation of the NF-kappaB inhibitor IkappaBalpha, but other molecular targets involved in T-cell signalling remained elusive. Here, we identify the CSN subunit 5 (CSN5) as a new interactor of Malt1 and Carma1. T-cell activation triggers the recruitment of the CSN to the CBM complex, and CSN downregulation impairs TCR-induced IKK activation. Furthermore, the CSN is required for maintaining the stability of Bcl10 in response to T-cell activation. Taken together, our data provide evidence for a functional link between the evolutionarily conserved CSN and the adaptive immunoregulatory CBM complex in T cells.
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PMID:COP9 signalosome controls the Carma1-Bcl10-Malt1 complex upon T-cell stimulation. 1944 10

Nuclear factor kappa enhancer binding protein (NF-kappaB) regulates diverse biological processes including immunity, inflammation, and apoptosis. A vast array of cellular stimuli converges on NF-kappaB, and ubiquitination plays an essential role in the coordination of these signals to regulate NF-kappaB activity. At least three steps in NF-kappaB activation directly involve ubiquitination: proteasomal degradation of inhibitor of NF-kappaB (IkappaB), processing of NF-kappaB precursors, and activation of the transforming growth factor (TGF)-beta-activated kinase (TAK1) and IkappaB kinase (IKK) complexes. In this review, we discuss recent advances in the identification and characterization of ubiquitination and deubiquitination machinery that regulate NF-kappaB. Particular emphasis is given to proteasome-independent functions of ubiquitin, specifically its role in the activation of protein kinase complexes and in coordination of cell survival and apoptosis signals downstream of tumor necrosis factor alpha (TNFalpha).
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PMID:The role of ubiquitin in NF-kappaB regulatory pathways. 1948 33

In prosthetic loosening, bone resorption is induced by wear debris particles generated from the artificial joint articulation. Our prior work showed that synovial-like fibroblasts respond to titanium particles by producing receptor activator of NF-kappaB ligand (RANKL), a critical activator of osteoclastogenesis. While this effect occurs through a cyclooxygenase-2 (COX-2)-dependent pathway, the mechanism of COX-2 stimulation by titanium particles is not clear. Here we show that titanium particles induce COX-2 gene expression by activating NF-kappaB signaling. Inhibitor of NF-kappaB (IkappaBalpha) is degraded following particle treatment, permitting active NF-kappaB to translocate to the nucleus where it interacts with the COX-2 promoter and drives transcription. NF-kappaB activation is dependent on reactive oxygen species since antioxidants block the NF-kappaB signaling induced by particles. Surprisingly, IkappaBalpha degradation is independent of IKK (IkappaB kinase) and the 26S proteasome. Instead, calpain inhibitor can block the IkappaBalpha degradation induced by particles. Furthermore, the calpain-targeted COOH-terminal PEST sequence of IkappaBalpha is necessary for phosphorylation and degradation, consistent with a proteasome-independent mechanism of catabolism. Altogether, the data demonstrate a signaling pathway by which titanium particles induce oxidative stress, stimulate calpain-mediated NF-kappaB activation, and activate target gene expression, including COX-2. These findings define important targets for osteolysis but may also have importance in other diseases where fibroblasts respond to environmental particles, including pulmonary diseases.
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PMID:Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-kappaB pathway. 1949 33

IkappaB kinase beta (IKKbeta), a major kinase downstream of various proinflammatory signals, mediates multiple cellular functions through phosphorylation and regulation of its substrates. On the basis of protein sequence analysis, we identified arrest-defective protein 1 (ARD1), a protein involved in apoptosis and cell proliferation processes in many human cancer cells, as a new IKKbeta substrate. We provided evidence showing that ARD1 is indeed a bona fide substrate of IKKbeta. IKKbeta physically associated with ARD1 and phosphorylated it at Ser209. Phosphorylation by IKKbeta destabilized ARD1 and induced its proteasome-mediated degradation. Impaired growth suppression was observed in ARD1 phosphorylation-mimic mutant (S209E)-transfected cells as compared with ARD1 non-phosphorylatable mutant (S209A)-transfected cells. Our findings of molecular interactions between ARD1 and IKKbeta may enable further understanding of the upstream regulation mechanisms of ARD1 and of the diverse functions of IKKbeta.
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PMID:Phosphorylation of ARD1 by IKKbeta contributes to its destabilization and degradation. 1971 9

Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor kappaB (NF-kappaB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-kappaB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-kappaB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or rendered zebrafish embryos more sensitive to the lethal effects of ionizing radiation (PS-341). Radiosensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-kappaB inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-kappaB inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system, and improved renal clearance compromised by radiation. In contrast to amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1 to 2 hours postexposure. Finally, four additional IkappaB kinase inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-kappaB activation may be useful in alleviating radiation toxicity in patients.
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PMID:Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos. 1972 85

The proinflammatory cytokine TNF-alpha exerts its pleiotropic functions through activation of multiple downstream effectors, including JNK1. Yet, the underlying regulatory mechanism is incompletely understood. Here, we report that the transcription factor Myc-interacting zinc-finger protein 1 (Miz1) selectively suppresses TNF-alpha-induced JNK1 activation and cell death independently of its transcription activity. Proteomics analysis and yeast two-hybrid screening reveal that Miz1 is a JNK-associated protein. The TNF-alpha-induced activation of JNK1 is augmented in Miz1-deficient mouse embryonic fibroblasts (Miz1(-/-) MEFs), but the augmentation is abrogated by reintroduction of Miz1 or its transcription-deficient mutant. The regulation by Miz1 is highly specific, because it regulates TNF-alpha-induced TRAF2 K63-linked polyubiquitination. Neither JNK1 activation by IL-1beta or UV nor TNF-alpha-induced activation of p38, ERK, or IkappaB kinase complex is affected by the loss of Miz1. The TNF-alpha-induced cell death also is accelerated in Miz1(-/-) MEFs. Upon TNF-alpha stimulation, Miz1 is degraded rapidly by the proteasome, relieving its suppression on JNK1 activation. Thus, our results show that in addition to being a transcription factor Miz1 acts as a signal- and pathway-specific modulator or regulator that specifically regulates TNF-alpha-induced JNK1 activation and cell death.
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PMID:Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-alpha-induced JNK1 activation. 1981 9

Metastasized melanoma is almost universally resistant to chemotherapy. Given that constitutive or drug-induced upregulation of NF-kappaB activity is associated with this chemoresistance, NF-kappaB inhibition may increase the susceptibility to antitumoral therapy. On the cellular level, two principles of NF-kappaB inhibition, proteasome inhibition by bortezomib and IkappaB kinase-beta (IKKbeta) inhibition by the kinase inhibitor of NF-kappaB-1 (KINK-1), significantly increased the antitumoral efficacy of camptothecin. When combined with camptothecin, either of the two NF-kappaB-inhibiting principles synergistically influenced progression-related in vitro functions, including cell growth, apoptosis, and invasion through an artificial basement membrane. In addition, when C57BL/6 mice were intravenously injected with B16F10 melanoma cells, the combination of cytostatic treatment with either of the NF-kappaB-inhibiting compounds revealed significantly reduced pulmonary metastasis compared to either treatment alone. However, on the molecular level, nuclear translocation of p65, cell cycle analysis, and expression of NF-kappaB-dependent gene products disclosed distinctly different molecular mechanisms, resulting in the same functional effect. That proteasome inhibition and IKKbeta inhibition affect distinct molecular pathways downstream of NF-kappaB, both leading to increased chemosensitivity, is previously unreported. Thus, it is conceivable that switching the two principles of NF-kappaB inhibition, once resistance to one of the agents occurs, will improve future treatment regimens.
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PMID:NF-kappaB inhibition through proteasome inhibition or IKKbeta blockade increases the susceptibility of melanoma cells to cytostatic treatment through distinct pathways. 1994 Aug 59

NF-kappaB (nuclear factor kappaB) has a pivotal role in many cellular processes, including the inflammatory and immune responses and, therefore, its activation is tightly regulated by the IKK (IkappaB kinase) complex and by IkappaBalpha degradation. When Shigella bacteria multiply within epithelial cells they release peptidoglycans, which are recognized by Nod1 and stimulate the NF-kappaB pathway, thus leading to a severe inflammatory response. Here, we show that IpaH9.8, a Shigella effector possessing E3 ligase activity, dampens the NF-kappaB-mediated inflammatory response to the bacterial infection in a unique way. IpaH9.8 interacts with NEMO/IKKgamma and ABIN-1, a ubiquitin-binding adaptor protein, promoting ABIN-1-dependent polyubiquitylation of NEMO. Consequently, polyubiquitylated NEMO undergoes proteasome-dependent degradation, which perturbs NF-kappaB activation. As NEMO is essential for NF-kappaB activation, we propose that the polyubiquitylation and degradation of NEMO during Shigella infection is a new bacterial strategy to modulate host inflammatory responses.
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PMID:A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. 2001 Aug 14

The mRNA and protein levels of aquaporin (AQP)5 in the parotid gland were found to be potentially decreased by lipopolysaccharide (LPS) in vivo in C3H/HeN mice, but only weakly in C3H/HeJ, a TLR4 mutant mouse strain. In the LPS-injected mice, pilocarpine-stimulated saliva production was reduced by more than 50%. In a tissue culture system, the LPS-induced decrease in the AQP5 mRNA level was blocked completely by pyrrolidine dithiocarbamate, MG132, tyrphostin AG126, SP600125, and partially by SB203580, which are inhibitors for IkappaB kinase, 26S proteasome, ERK1/2, JNK, and p38 MAPK, respectively. In contrast, the expression of AQP1 mRNA was down-regulated by LPS and such down-regulation was blocked only by SP600125. The transcription factors NF-kappaB (p65 subunit), p-c-Jun, and c-Fos were increased by LPS given in vivo, whereas the protein-binding activities of the parotid gland extract toward the sequences for NF-kappaB but not AP-1-responsive elements present at the promoter region of the AQP5 gene were increased by LPS injection. Co-immunoprecipitation by using antibody columns suggested the physical association of the three transcription factors. These results suggest that LPS-induced potential down-regulation of expression of AQP5 mRNA in the parotid gland is mediated via a complex(es) of these two classes of transcription factors, NF-kappaB and p-c-Jun/c-Fos.
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PMID:Potential down-regulation of salivary gland AQP5 by LPS via cross-coupling of NF-kappaB and p-c-Jun/c-Fos. 2052 48


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