Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of HeLa cells with tumour necrosis factor alpha (TNFalpha) induced caspase processing of ectopic PKC (protein kinase C) zeta, which converted most of the holoenzyme into the freed kinase domain and increased immune-complex kinase activity. The goal of the present study was to determine the basis for the increased kinase activity that is associated with caspase processing of PKC zeta. Atypical PKC iota is largely identical with PKC zeta, except for a 60-amino-acid segment that lacks the caspase-processing sites of the zeta isoform. Replacement of this segment of PKC zeta with the corresponding segment of PKC iota prevented caspase processing and activation of the kinase function. Processing of purified recombinant PKC zeta by caspase 3 in vitro markedly increased its kinase activity. Caspase processing activated PKC zeta in vitro or intracellularly without increasing the phosphorylation of Thr410 of PKC zeta, which is required for catalytic competency. The freed kinase domain of PKC zeta had a much shorter half-life than the holoenzyme in transfected HeLa cells and in non-transfected kidney epithelial cells. Treatment with TNF-alpha shortened the half-life of the kinase domain protein, and proteasome blockade stabilized the protein. Studies of kinase-domain mutants indicate that a lack of negative charge at Thr410 can shorten the half-life of the freed kinase domain. The present findings indicate that the freed kinase domain has substantially higher kinase activity and a much shorter half-life than the holoenzyme because of accelerated degradation by the ubiquitin-proteasome system.
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PMID:Caspase processing activates atypical protein kinase C zeta by relieving autoinhibition and destabilizes the protein. 1288 31

In order to investigate any effect of mutant huntingtin aggregation on proteasome function and the degradation of proteins involved in the ubiquitin-proteasome pathway, we studied the degradation of PKCalpha in Neuro2a cells expressing either normal or mutant truncated huntingtin (HD 16Q and HD 150Q cells). We were able to show an elevation of polyubiquitinated PKCalpha in HD 150Q cells. PMA treatment of these cells revealed significant delay of PKCalpha degradation in comparison with control HD 16Q cells. Subcellular fractionation showed association of non-degraded PKCalpha with the membrane fraction of HD 150Q cells. Our data suggest an impairment of the degradation of PKCalpha in HD 150Q cells. This impairment is likely to be connected with the sequestration of proteasome on mutant huntingtin aggregates.
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PMID:Impaired degradation of PKCalpha by proteasome in a cellular model of Huntington's disease. 1296 Jul 59

The dioxin receptor (AhR), in addition to its role in xenobiotic-induced carcinogenesis, appears to participate in cell proliferation, differentiation and organ homeostasis. Understanding potential mechanisms of activation of this receptor in the absence of exogenous ligands is therefore important to study its contribution to endogenous cellular functions. Using mouse embryo primary fibroblasts, we have previously shown that proteasome inhibition increased AhR transcriptional activity in the absence of xenobiotics. We suggested that proteasome inhibition-dependent AhR activation could involve an increase in the expression of the partner protein dioxin receptor nuclear translocator (ARNT). Since ARNT over-expression induced nuclear translocation of the AhR, and ARNT-deficient cells were unable to translocate this receptor to the nucleus upon proteasome inhibition, we have analyzed the effect of proteasome inhibition on the expression of regulatory proteins controlling ARNT levels. Treatment with the proteasome inhibitor MG132 increased endogenous Sp1 phosphorylation and its DNA-binding activity to the ARNT promoter. Sp1 phosphorylation and binding to the ARNT promoter, ARNT over-expression and AhR nuclear translocation were inhibited by GF109203X, a protein kinase C-specific inhibitor. In addition, MG132 stimulated protein kinase C activity in MEF cells with a pattern similar to that observed for ARNT expression. These data suggest that cellular control of protein kinase C activity, through Sp1 and ARNT, could regulate AhR transcriptional activity in the absence of xenobiotics.
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PMID:Proteasome inhibition induces nuclear translocation of the dioxin receptor through an Sp1 and protein kinase C-dependent pathway. 1452 14

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.
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PMID:The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. 1455 44

2'-5' Oligoadenylate (2-5A)-dependent RNase L is one of the key enzymes involved in the molecular mechanisms of interferon (IFN) function. Although the regulation of RNase L by 2-5A has been studied extensively, relatively little is known about how RNase L is controlled by posttranslational processes. Here, we report that phorbol-12-myristate-13-acetate (PMA) treatment of mouse L929 fibroblasts caused rapid degradation of RNase L in a dose-dependent and time-dependent manner. RNase L levels were decreased to 40% of control levels after only 5 min exposure of cells to PMA, suggesting the involvement of protein kinase C (PKC). After PMA treatment for 1 h, RNase L levels decreased to 18% of the pretreatment levels. Decay of RNase L was measured by 2-5A binding assay, ribonuclease activity, and protein levels in Western blots probed with antibody to murine RNase L. PMA treatment caused decreases in the levels of RNase L in both cytoplasm and nucleus. To explore the mechanism of RNase L degradation, we treated cells with the selective proteasome inhibitors, ALLN, MG132, and PSI, prior to PMA treatment. These inhibitors completely blocked the degradation of RNase L caused by PMA. Our results show a novel regulatory pathway for RNase L that could have an impact on its antitumor and antiviral functions.
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PMID:Proteasome-mediated degradation of RNase L in response to phorbol-12-myristate-13-acetate (PMA) treatment of mouse L929 cells. 1458 96

Signal transduction pathways are controlled by desensitization mechanisms, which can affect receptors and/or downstream signal transducers. It has long been recognized that members of the protein kinase C (PKC) family of signal transduction molecules undergo down-regulation in response to activation. Previous reports have indicated that key steps in PKCalpha desensitization include caveolar internalization, priming site dephosphorylation, ubiquitination of the dephosphorylated protein, and degradation by the proteasome. In the current study, comparative analysis of PKCalpha processing induced by the PKC agonists phorbol 12-myristate 13-acetate and bryostatin 1 in IEC-18 rat intestinal epithelial cells demonstrates that: (a) at least two pathways of PKCalpha down-regulation can co-exist within cells, and (b) a single PKC agonist can activate both pathways at the same time. Using a combined biochemical and morphological approach, we identify a novel pathway of PKCalpha desensitization that involves ubiquitination of mature, fully phosphorylated activated enzyme at the plasma membrane and subsequent down-regulation by the proteasome. The phosphatase inhibitors okadaic acid and calyculin A accelerated PKCalpha down-regulation and inhibitors of vesicular trafficking did not prevent degradation of the protein, indicating that neither internalization nor priming site dephosphorylation are requisite intermediate steps in this ubiquitin/proteasome dependent pathway of PKCalpha down-regulation. Instead, caveolar trafficking and dephosphorylation are involved in a second, proteasome-independent mechanism of PKCalpha desensitization in this system. Our findings highlight subcellular distribution and phosphorylation state as critical determinants of PKCalpha desensitization pathways.
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PMID:Identification of two distinct pathways of protein kinase Calpha down-regulation in intestinal epithelial cells. 1463 91

The levels of protein kinase C-gamma (PKC-gamma ) and the calcium/calmodulin-dependent kinase II-alpha (CaMKII-alpha) were measured in crude synaptosomal (P2), particulate (P3), and cytosolic (S3) fractions of the neocortex of rats exposed to 1-hour and 2-hour middle cerebral artery occlusion (MCAO) and 2-hour MCAO followed by 2-hour reperfusion. During MCAO, PKC levels increased in P2 and P3 in the most severe ischemic areas concomitantly with a decrease in S3. In the penumbra, PKCgamma decreased in S3 without any significant increases in P2 and P3. Total PKC-gamma also decreased in the penumbra but not in the ischemic core, suggesting that the protein is degraded by an energy-dependent mechanism, possibly by the 26S proteasome. The CaMKII-alpha levels increased in P2 but not P3 during ischemia and reperfusion in all ischemic regions, particularly in the ischemic core. Concomitantly, the levels in S3 decreased by 20% to 40% in the penumbra and by approximately 80% in the ischemic core. There were no changes in the total levels of CaMKII-alpha during MCAO. The authors conclude that during and after ischemia, PKC and CaMKII-alpha are translocated to the cell membranes, particularly synaptic membranes, where they may modulate cellular function, such as neurotransmission, and also affect cell survival. Drugs preventing PKC and/or CaMKII-alpha translocation may prove beneficial against ischemic cell death.
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PMID:Protein kinase C-gamma and calcium/calmodulin-dependent protein kinase II-alpha are persistently translocated to cell membranes of the rat brain during and after middle cerebral artery occlusion. 1468 16

The balance between polymorphonuclear leukocytes (PMNL) apoptosis and necrosis in inflamed tissues is an important determinant of the degree of tissue injury. To prevent senescent PMNL from releasing their toxic contents into surrounding tissues, these cells become apoptotic and are then internalized by tissue macrophages. PMNL apoptosis and subsequent ingestion by macrophages are the major mechanisms for clearing PMNL that have been recruited to the inflamed sites and thus for promoting resolution of the inflammation. PMNL have a short half-life that is extended at the inflamed site by pro-inflammatory cytokines including Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interleukin-8 (IL-8), Gro-alpha, and they contact with the bacterial cell walls containing lipopolysaccharides (LPS). Conversely, anti-inflammatory cytokines, such as IL-10, accelerate the apoptosis of LPS-activated PMNL. Spontaneous PMNL apoptosis does not require Fas ligation but involves proteolytic cascades -caspases (particularly caspases 3 and 8), calpains and the proteasome-that activate kinases, e.g. caspase 3-mediated activation of protein kinase C-delta, dissociate actin-binding proteins from filamentous actin, and participate in cell surface as well as nuclear morphological transformations. Members of the Bcl-2 protein family, Mcl-1 and A1, are involved in the regulation of PMNL apoptosis. Cell surface receptors and protein kinases, particularly mitogen-activated protein kinases (MAPK), also play critical roles in transducing the signals that result in PMNL apoptosis or extended survival. A growing understanding of the mechanisms regulating leukocyte apoptosis and of the molecules mediating safe phagocytic clearance of dying cells may yield new insights into the pathogenesis of inflammatory diseases. In this regard, therapeutic strategies to resolve chronic inflammation could usefully target PMNL. This review summarises current knowledge on the molecular mechanisms and components of PMNL apoptosis.
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PMID:Molecular regulation of neutrophil apoptosis and potential targets for therapeutic strategy against the inflammatory process. 1503 37

The involvement of phospholipase D (PLD) in the regulation of melanogenesis was examined. Treatment of B16 mouse melanoma cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in the activation of PLD and a decrease in melanin content. 1-Butanol, but not 2-butanol, completely blocked the TPA-induced inhibition of melanogenesis, suggesting the involvement of PLD in this event. Reverse transcription-PCR and immunoblot analyses revealed the existence of both PLD isozymes, PLD1 and PLD2, in B16 cells. When PLD1 or PLD2 was introduced into those cells by an adenoviral gene-transfer technique, both PLD1 and PLD2 were activated by TPA. When PLD1 and PLD2 were overexpressed, PLD2 potently caused a decrease in melanin content, whereas the effect of PLD1 expression on melanin content was minimal. Over-expression of PLD2 itself did not affect protein kinase C activity, as assessed by the intracellular distribution and levels of expression of each isoform expressed in B16 cells. The effects of TPA on the down-regulation of basal or alpha-melanocyte-stimulating hormone-enhanced melanogenesis were almost completely blocked by expressing a lipase activity-negative mutant, LN-PLD2, but not by LN-PLD1. Further, the PLD2-induced decrease in melanin content was accompanied by a decrease in the amount and activity of tyrosinase, a key enzyme in melanogenesis, whereas the mRNA level of tyrosinase was unchanged by the over-expression of PLD2. Moreover, treatment with proteasome inhibitors completely blocked the PLD2-induced down-regulation of melanogenesis. Taken together, the present results indicate that the TPA-induced down-regulation of melanogenesis is mediated by PLD2 but not by PLD1 through the ubiquitin proteasome-mediated degradation of tyrosinase. This suggests that PLD2 may play an important role in regulating pigmentation in vivo.
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PMID:Down-regulation of melanogenesis by phospholipase D2 through ubiquitin proteasome-mediated degradation of tyrosinase. 1506 2

Bcl10 is a critical regulator of NF-kappa B activity in T and B cells, coupling antigen receptor signaling to NF-kappa B activation via protein kinase C (PKC). Here we show that PKC or T-cell receptor (TCR)/CD28 signaling results in downregulation of Bcl10 protein levels, thereby attenuating NF-kappa B transcriptional activity. Bcl10 degradation requires an intact caspase recruitment domain and is not observed after stimulation with tumor necrosis factor alpha or lipopolysaccharides. Bcl10 downregulation is not affected by proteasome inhibitors but is accompanied by transient localization to lysosomal vesicles, suggesting involvement of the lysosomal pathway rather than the proteasome. The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation. Since CD3/CD28-induced activation of JNK is not affected by the decline of Bcl10, degradation of Bcl10 selectively terminates IKK/NF-kappa B signaling in response to TCR stimulation. Together, these results suggest a new mechanism of negative signaling in which TCR/PKC signaling initially activates Bcl10 but later promotes its degradation.
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PMID:Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling. 1508 80


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