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 regulation of cell cycle progression is a complex process which involves kinase cascades, protease action, production of second messengers and other operations. Increasing evidence now compellingly suggests that changes in the intracellular Ca2+ concentration may also have a crucial role. Ca2+ transients occur at the awakening from quiescence, at the G/S transition, during S-phase, and at the exit from mitosis. They may lead to the activation of Ca2+ binding proteins like S-100, but the key decoder of the Ca2+ signals in the cycle is calmodulin. Activation of calmodulin leads to the stimulation of protein kinases, i.e., CaM-kinase II, and of the CaM-dependent protein phosphatase calcineurin. Ample evidence now indicates the G/S transition, the progression from G2 to M, and the metaphase/anaphase transition as specific points of intervention of CaM-kinase II. Another attractive possibility for the role of Ca2+ in the cycle is through the activation of the Ca(2+)-dependent protease calpain: other proteases (e.g., the proteasome) have been suggested to be responsible for the degradation of some of cyclins, which is essential to the progression of the cycle. One of the cyclins, however, (D1) is instead degraded by calpain, which has been shown to promote both mitosis and meiosis when injected into somatic cells or oocytes.
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PMID:The role of calcium in the cell cycle: facts and hypotheses. 951 55

Oxidants cause activation of the AP-1 transcription factor in cardiomyocytes. c-Fos, a component of the AP-1 transcription factor, is transiently induced by H2O2 and the induction is sensitive to the protein synthesis inhibitor cycloheximide. With high percentage gel electrophoresis, multiple c-Fos bands were resolved by Western blot analyses, indicating post-translational modification of newly synthesized c-Fos protein after H2O2 exposure. Treatment of immunoprecipitated c-Fos protein with the type 2 serine/threonine phosphatase A (PP2A) and immunoblotting of c-Fos protein with antibodies against phosphorylated serine or threonine demonstrated that c-Fos was phosphorylated at serine residues. A pharmacological inhibitor of JNKs inhibited the formation of multiple c-Fos bands without affecting c-fos transcription. The proteasomal inhibitor MG132 and Proteasome Inhibitor I extended the time course of c-Fos protein elevation. An increase in ubiquitin was detectable in c-Fos protein from H2O2-treated cells. Interestingly, treating the whole cell lysates with PP2A, but not calcineurin (i.e. PP2B), resulted in disappearance of c-Fos protein and MG132 was able to prevent this loss. H2O2 caused an elevation of PP2B and total phosphatase activity. The phosphatase inhibitor okadaic acid, but not PP2B inhibiter cypermethrin, extended the time course of c-Fos protein elevation after H2O2 exposure. These data suggest that JNK-mediated phosphorylation of newly synthesized c-Fos protects the protein from being degraded by the proteasome. PP2B independent dephosphorylation contributes to degradation of c-Fos protein during oxidative stress response of cardiomyocytes.
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PMID:c-Fos phosphorylation induced by H2O2 prevents proteasomal degradation of c-Fos in cardiomyocytes. 1513 64

Connexin 43 (Cx43), a primary component of gap junctions, contributes to intercellular electrochemical communication. Cx43 undergoes dephosphorylation in early ischemia. We examined whether Cx43 is degraded in association with dephosphorylation during early myocardial ischemia and whether ischemic preconditioning (IP) affects the degradation after rat coronary artery occlusion. Male Sprague-Dawley rats underwent coronary artery occlusion for 1, 2, or 3 hours, or for 1 hour following treatment either with a calcineurin inhibitor (cyclosporine A), proteasome inhibitor (PSI), or lysosomal inhibitor (E64c), or following IP alone or after protein kinase C (PKC) inhibitor (chelerythrine) pretreatment. The IP was afforded by three cycles of 3 minute ischemia and 5 minute reperfusion. A large portion of the phosphorylated Cx43 (pCx43) in the membrane fraction was dephosphorylated, while a small portion was degraded at 1 hour of ischemia. The effects of the inhibitors were dephosphorylation and degradation by calcineurin and proteasome/lysosome, respectively. IP suppressed the decrease in pCx43 and increase in dCx43, while only the former was inhibited by the PKC inhibitor chelerythrine. The Cx43 mRNA level was reduced at 3 hours, but not at 1 hour of ischemia, irrespective of IP. We believe that Cx43 is dephosphorylated and degraded in early ischemia, whereas Cx43 transcription was suppressed at a later phase of ischemia.
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PMID:Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in vivo. 1565 76

Stimulation of primary human T lymphocytes results in up-regulation of cyclin T1 expression, which correlates with phosphorylation of the C-terminal domain of RNA polymerase II (RNAP II). Up-regulation of cyclin T1 and concomitant stabilization of cyclin-dependent kinase 9 (CDK9) may facilitate productive replication of HIV in activated T cells. We report that treatment of PBLs with two mitogens, PHA and PMA, results in accumulation of cyclin T1 via distinct mechanisms. PHA induces accumulation of cyclin T1 mRNA and protein, which results from cyclin T1 mRNA stabilization, without significant change in cyclin T1 promoter activity. Cyclin T1 mRNA stabilization requires the activation of both calcineurin and JNK because inhibition of either precludes cyclin T1 accumulation. In contrast, PMA induces cyclin T1 protein up-regulation by stabilizing cyclin T1 protein, apparently independently of the proteasome and without accumulation of cyclin T1 mRNA. This process is dependent on Ca2+-independent protein kinase C activity but does not require ERK1/2 activation. We also found that PHA and anti-CD3 Abs induce the expression of both the cyclin/CDK complexes involved in RNAP II C-terminal domain phosphorylation and the G1-S cyclins controlling cell cycle progression. In contrast, PMA alone is a poor inducer of the expression of G1-S cyclins but often as potent as PHA in inducing RNAP II cyclin/CDK complexes. These findings suggest coordination in the expression and activation of RNAP II kinases by pathways that independently stimulate gene expression but are insufficient to induce S phase entry in primary T cells.
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PMID:Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. 1627 92

The Ca2+-activated pathways in Saccharomyces cerevisiae induce a delay in the onset of mitosis through the activation of Swe1p, a negative regulatory kinase that inhibits the Cdc28p/Clb complex. We isolated the YAP1 gene as a multicopy suppressor of calcium sensitivity owing to the loss of ZDS1, a negative regulator of SWE1 and CLN2 gene expression. YAP1 deletion on a zds1delta background exacerbated the Ca2+-related phenotype. Yap1p was degraded in a calcineurin-dependent manner when cells were exposed to calcium. In yap1delta cells, the expression level of the RPN4 gene encoding a transcription factor for the subunits of the ubiquitin-proteasome system was diminished. The deletion of YAP1 gene or RPN4 gene led to the accumulation of Swe1p and Cln2p. Yap1p was a substrate of calcineurin in vivo and in vitro. The calcineurin-mediated Yap1p degradation seems to be a long adaptive response that assures a G2 delay in response to a stress that causes the activation of the calcium signalling pathways.
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PMID:Involvement of calcineurin-dependent degradation of Yap1p in Ca2+-induced G2 cell-cycle regulation in Saccharomyces cerevisiae. 1648 23

Hyperphosphorylated tau proteins accumulate in the paired helical filaments of neurofibrillary tangles seen in such tauopathies as Alzheimer's disease. In the present paper we show that tau turnover is dependent on degradation by the proteasome (inhibited by MG132) in HT22 neuronal cells. Recombinant human tau was rapidly degraded by the 20 S proteasome in vitro, but tau phosphorylation by GSK3beta (glycogen synthase kinase 3beta) significantly inhibited proteolysis. Tau phosphorylation was increased in HT22 cells by OA [okadaic acid; which inhibits PP (protein phosphatase) 1 and PP2A] or CsA [cyclosporin A; which inhibits PP2B (calcineurin)], and in PC12 cells by induction of a tet-off dependent RCAN1 transgene (which also inhibits PP2B). Inhibition of PP1/PP2A by OA was the most effective of these treatments, and tau hyperphosphorylation induced by OA almost completely blocked tau degradation in HT22 cells (and in cell lysates to which purified proteasome was added) even though proteasome activity actually increased. Many tauopathies involve both tau hyperphosphorylation and the oxidative stress of chronic inflammation. We tested the effects of both cellular oxidative stress, and direct tau oxidative modification in vitro, on tau proteolysis. In HT22 cells, oxidative stress alone caused no increase in tau phosphorylation, but did subtly change the pattern of tau phosphorylation. Tau was actually less susceptible to direct oxidative modification than most cell proteins, and oxidized tau was degraded no better than untreated tau. The combination of oxidative stress plus OA treatment caused extensive tau phosphorylation and significant inhibition of tau degradation. HT22 cells transfected with tau-CFP (cyan fluorescent protein)/tau-GFP (green fluorescent protein) constructs exhibited significant toxicity following tau hyperphosphorylation and oxidative stress, with loss of fibrillar tau structure throughout the cytoplasm. We suggest that the combination of tau phosphorylation and tau oxidation, which also occurs in tauopathies, may be directly responsible for the accumulation of tau aggregates.
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PMID:Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. 1693 15

While the role of the ubiquitin-proteasome system (UPS) in regulating cellular processes continues to expand, the elucidation of its role in cardiac disease is just beginning. The UPS regulates pivotal processes at all levels of cardiac biology: from membrane-associated ion channels and receptors to downstream signaling intermediates and transcription factors. Moreover, the role of the UPS in maintaining cardiac protein quality control is emerging, as exemplified by its multiple interactions with the cardiac sarcomere and role in familial cardiomyopathies. The diversity of UPS regulation lies in E3 ligases, which specifically recognize targets and direct the ubiquitination process. In the context of disease, E3 ligase expression affects the severity of disease in both ischemia reperfusion injury and cardiac hypertrophy in vivo by modulating signaling intermediates. In ischemia-reperfusion injury, the activities of CHIP and MDM2 (both with E3 ligase activity) profoundly affect apoptosis regulation and severity of disease. In cardiac hypertrophy, Atrogin1 and MuRF1 attenuate cardiac hypertrophy by interacting with calcineurin and PKCepsilon, respectively. Additionally, MuRF1 and MDM2 interact with sarcomeric proteins (cTnI and Tcap, respectively) which may prove to be mechanisms by which hypertrophy is attenuated or protein quality modulated. All of these exciting new findings, however, must be taken in the context of disease regulation of the UPS components themselves. Key UPS components (e.g. ubiquitin, E1, E2, E3, proteasome) are themselves transcriptionally regulated in cardiac disease. Our understanding of the precise nature by which the UPS regulates key biological functions in cardiac disease has just begun.
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PMID:Into the heart: the emerging role of the ubiquitin-proteasome system. 1694 2

The entorhinal cortex (EC) serves as a gateway to the hippocampus and plays a pivotal role in memory processing in the brain. Superficial layers of the EC convey the cortical input projections to the hippocampus, whereas deep layers of the EC relay hippocampal output projections back to the superficial layers of the EC or to other cortical regions. Whereas the EC expresses long-term potentiation (LTP) and depression (LTD), the underlying cellular and molecular mechanisms have not been determined. Because the axons of the stellate neurons in layer II of the EC form the perforant path that innervates the dentate gyrus granule cells of the hippocampus, we studied the mechanisms underlying the long-term plasticity in identified stellate neurons. Application of high-frequency stimulation (100 Hz for 1 s, repeated 3 times at an interval of 10 s) or forskolin (50 microM) failed to induce significant changes in synaptic strength, whereas application of pairing (presynaptic stimulation at 0.33 Hz paired with postsynaptic depolarization from -60 to -10 mV for 5 min) or low-frequency stimulation (LFS, 1 Hz for 15 min) paradigm-induced LTD. Pairing- or LFS-induced LTDs were N-methyl-D-aspartate receptor-dependent and occluded each other suggesting that they have the similar cellular mechanism. Pairing-induced LTD required the activity of calcineurin and involved AMPA receptor endocytosis that required the function of ubiquitin-proteasome system. Our study provides a cellular mechanism that might in part explain the role of the EC in memory.
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PMID:Long-term depression in identified stellate neurons of juvenile rat entorhinal cortex. 1713 66

Oxygen homeostasis represents an essential organizing principle of metazoan evolution and biology. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of transcriptional responses to changes in O2 concentration. HIF-1 is a heterodimer of HIF-1alpha and HIF-1beta subunits. O2-dependent degradation of the HIF-1alpha subunit is mediated by prolyl hydroxylase, von Hippel-Lindau protein (VHL)/Elongin-C E3 ubiquitin ligase, and the proteasome. O2-independent degradation of HIF-1alpha is regulated by the competition of RACK1 and HSP90 for binding to HIF-1alpha. RACK1 binding results in the recruitment of the Elongin-C E3 ubiquitin ligase, leading to VHL-independent ubiquitination and degradation of HIF-1alpha. In this report, we show that calcineurin inhibits the ubiquitination and proteasomal degradation of HIF-1alpha. Calcineurin is a serine/threonine phosphatase that is activated by calcium and calmodulin. The phosphatase activity of calcineurin is required for its regulation of HIF-1alpha. RACK1 binds to the catalytic domain of calcineurin and is required for HIF-1alpha degradation induced by the calcineurin inhibitor cyclosporine A. Elongin-C and HIF-1alpha each bind to RACK1 and dimerization of RACK1 is required to recruit Elongin-C to HIF-1alpha. Phosphorylation of RACK1 promotes its dimerization and dephosphorylation by calcineurin inhibits dimerization. Serine 146 within the dimerization domain is phosphorylated and mutation of serine 146 impairs RACK1 dimerization and HIF-1alpha degradation. These results indicate that intracellular calcium levels can regulate HIF-1alpha expression by modulating calcineurin activity and RACK1 dimerization.
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PMID:Calcineurin promotes hypoxia-inducible factor 1alpha expression by dephosphorylating RACK1 and blocking RACK1 dimerization. 1796 24

Poly-ubiquitin chains are post-translational modifications commonly used by the ubiquitin-proteasome system to mark proteins for degradation. The regulation of protein degradation plays an important role in regulating muscle cell size, a cellular process balanced by protein synthesis and catabolism. MaFBx/Atrogin-1, a muscle specific F-box protein, is a principle component of the SCF(atrogin-1) ubiquitin ligase complex that ubiquitinates and targets calcineurin for degradation, a key regulatory protein involved in pathologic hypertrophy. We have recently described a novel role for this ubiquitin ligase as a co-activator of the FOXO transcription factors through the catalysis of non-canonical poly-ubiquitin chain formation on FOXO proteins, an event that is sufficient to block Akt-dependent pathways involved in physiologic hypertrophy. In context with other reports describing the regulation and role of FOXO transcription factors, we present a working model for the role of atrogin-1 in both physiologic and pathologic hypertrophy.
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PMID:You spin me round: MaFBx/Atrogin-1 feeds forward on FOXO transcription factors (like a record). 1823 41


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