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 system plays key roles in the control of cell growth. The cell cycle, in particular, is highly regulated by the functions of the SCF and APC/C ubiquitin ligases, and perturbation of their function can result in tumorigenesis. Although the SCF and APC/C complexes are well established in growth control pathways, many aspects of their function remain unknown. Recent studies have shed light on the mechanism of SCF-mediated ubiquitination and new functions for the SCF complex and APC/C. Our expanding understanding of the roles of the SCF and APC/C complexes highlight the potential for targeted molecular therapies.
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PMID:Control of cell growth by the SCF and APC/C ubiquitin ligases. 1977 79

The anaphase-promoting complex (APC/C), a ubiquitin ligase, is the target of the spindle-assembly checkpoint (SAC), and it ubiquitylates protein substrates whose degradation regulates progress through mitosis. The identity of the ubiquitin-conjugating (E2) enzymes that work with the APC/C is unclear. In an RNA interference (RNAi) screen for factors that modify release from drug-induced SAC activation, we identified the E2 enzyme UBE2S as an APC/C auxiliary factor that promotes mitotic exit. UBE2S is dispensable in a normal mitosis, but its depletion prolongs drug-induced mitotic arrest and suppresses mitotic slippage. In vitro, UBE2S elongates ubiquitin chains initiated by the E2 enzymes UBCH10 and UBCH5, enhancing the degradation of APC/C substrates by the proteasome. Indeed, following release from SAC-induced mitotic arrest, UBE2S-depleted cells neither degrade crucial APC/C substrates, nor silence this checkpoint, whereas bypassing the SAC through BUBR1 depletion or Aurora-B inhibition negates the requirement for UBE2S. Thus, UBE2S functions with the APC/C in a two-step mechanism to control substrate ubiquitylation that is essential for mitotic exit after prolonged SAC activation, providing a new model for APC/C function in human cells.
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PMID:UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. 1982 Jul 2

Proteasome-mediated proteolysis is responsible for the generation of immunogenic epitopes presented by MHC class I molecules, which activate antigen-specific CD8+ T cells. Immunoproteasomes, defined by the presence of the three catalytic subunits LMP2, MECL-1, and LMP7, have been hypothesized to optimize MHC class I antigen processing. In this study, we demonstrate that the infection of mice with a protozoan parasite, Toxoplasma gondii, induced the expression of LMP7 mRNA in APC and increased the capacity of APC to induce the production of IFN-gamma by antigen-specific CD8+ T cells. In vitro infection of a DC cell line with T. gondii also induced the expression of LMP7 and resulted in enhanced proteasome proteolytic activity. Finally, mice lacking LMP7 were highly susceptible to infection with T. gondii and showed a reduced number of functional CD8+ T cells. These results demonstrate that proteasomes containing LMP7 play an indispensable role in the survival of mice infected with T. gondii, presumably due to the efficient generation of CTL epitopes required for the functional development of CD8+ T cells.
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PMID:Critical role for the immunoproteasome subunit LMP7 in the resistance of mice to Toxoplasma gondii infection. 1983 Jul 24

The anaphase-promoting complex/cyclosome (APC/C) is essential for progression through mitosis. At anaphase onset, the APC/C requires the activator protein CDC20 to target securin and cyclin B1 for proteasome-dependent degradation, but then depends on the CDC20-related protein FZR1 (also known as CDH1) to remain active until the onset of the next S phase. To investigate the role of FZR1 in mammalian cells, we used RNAi in human cell lines and conditional gene targeting in mouse embryonic fibroblasts. In neither case was FZR1 required for exit from mitosis, but in cells lacking FZR1, the G1 phase was shortened and the S phase was prolonged. In several normal and transformed human cell lines, loss of FZR1 function induced DNA-damage responses and impaired proliferation independently of the p53 status. Constitutive knockdown of p53 in U2OS cells with inducible FZR1 siRNA also failed to restore their proliferative capacity. Thus, the proliferation defects are a direct consequence of the genetic damage inflicted by loss of FZR1 function and are largely independent of p53. In summary, mammalian FZR1 is not required for the completion of mitosis, but is an important regulator of G1 phase and is required for efficient DNA replication in human and mouse somatic cells.
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PMID:Loss of the mammalian APC/C activator FZR1 shortens G1 and lengthens S phase but has little effect on exit from mitosis. 1986 96

The T cell-specific tyrosine kinase, p56(lck), plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56(lck). SOCS-6 was identified as a protein binding to the kinase domain of p56(lck) through yeast two-hybrid screening. SOCS-6 bound specifically to p56(lck) (F505), which mimics the active form of p56(lck), but not to wild type p56(lck). In Jurkat T cells, SOCS-6 binding to p56(lck) was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56(lck). SOCS-6 promoted p56(lck) ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.
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PMID:SOCS-6 negatively regulates T cell activation through targeting p56lck to proteasomal degradation. 2000 9

Progression through mitosis and cytokinesis requires the sequential proteolysis of several cell-cycle regulators. This proteolysis is mediated by the ubiquitin-proteasome system, with the E3 ligase being the anaphase-promoting complex, also known as the cyclosome (APC/C). The APC/C is regulated by two activators, namely Cdc20 and Cdh1. The current view is that prior to anaphase, the APC/C is activated by Cdc20, but that following anaphase, APC/C switches to Cdh1-dependent activation. However, here we present an analysis of the kinetochore protein Cenp-F that is inconsistent with this notion. Although it has long been appreciated that Cenp-F is degraded sometime during or after mitosis, exactly when and how has not been clear. Here we show that degradation of Cenp-F initiates about six minutes after anaphase, and that this is dependent on a C-terminal KEN-box. Although these two observations are consistent with Cenp-F being a substrate of Cdh1-activated APC/C, Cenp-F is degraded normally in Cdh1-null cells. By contrast, RNAi-mediated repression of APC/C subunits or Cdc20 does inhibit Cenp-F degradation. These findings therefore suggest that the APC/C does not simply 'switch' upon anaphase onset; rather, our observations indicate that Cdc20 also contributes to post-anaphase activation of the APC/C. We also show that the post-anaphase, KEN-box-dependent degradation of Cenp-F requires it to be farnesylated, a post-translational modification usually linked to membrane association. Because so many of the behaviours of Cenp-F are farnesylation-dependent, we suggest that this modification plays a more global role in Cenp-F function.
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PMID:Cdc20 is required for the post-anaphase, KEN-dependent degradation of centromere protein F. 2005 38

Cdc20, an activator of the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase, initiates the destruction of key mitotic regulators to facilitate mitosis, while it is negatively regulated by the spindle assembly checkpoint (SAC) to prevent premature anaphase entry. Activation of the p38 mitogen-activated protein kinase could contribute to mitotic arrest, but the underlying mechanism is unknown. Here we report a novel pathway in which the p38 signaling triggers Cdc20 destruction under SAC elicited by cadmium, a human carcinogen. We found that the cadmium-induced prometaphase arrest was linked to decreased Cdc20 and accumulated cyclin A protein levels in human cells, whereas the activity of cyclin B1-Cdk1 was unaffected. The Cdc20 half-life was markedly shortened along with its ubiquitination and degradation via 26S proteasome in cadmium-treated asynchronous or G(2)-enriched cells. Depletion of APC3 markedly suppressed the cadmium-induced Cdc20 ubiquitination and proteolysis, while depletion of Cdh1, another activator of APC/C, did not. Intriguingly, blockage of p38 activity restored the Cdc20 levels for continuing mitosis under cadmium, while inhibition of JNK activity had no effect. The cadmium-induced Cdc20 proteolysis was also suppressed during transient depletion of p38alpha or stable expression a dominant negative form of p38. Inhibition of p38 abolished the induction of Mad2-Cdc20-APC3 complex by cadmium. Moreover, forced expression of MKK6-p38 signaling could promote Cdc20 degradation in a Cdh1-independent APC/C pathway. In summary, accelerated ubiquitination and proteolysis of Cdc20 is essential for prometaphase arrest that is mediated via the p38 signaling during SAC activation.
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PMID:Cdc20 proteolysis requires p38 MAPK signaling and Cdh1-independent APC/C ubiquitination during spindle assembly checkpoint activation by cadmium. 2005 26

We have recently demonstrated that TRB3, a novel endoplasmic reticulum (ER) stress-inducible protein, is induced by CHOP and ATF4 to regulate their function and ER stress-induced cell death; however, the regulation of TRB3 function has not been well characterized. Here we demonstrate that TRB3 is an unstable protein regulated by the ubiquitin-proteasome system. The carboxyl-terminal domain of TRB3 is necessary for protein degradation, and in this region, we found the typical D-box motif, which is a critical sequence for the anaphase-promoting complex/cyclosome (APC/C) dependent proteolysis. TRB3 proteins were stabilized by deletion of its D-box motif and interacted with APC/C coactivator proteins, Cdc20 and Cdh1. The expression level of TRB3 protein is down-regulated by over-expression of Cdh1 but not by that of Cdc20. In addition, knockdown of Cdh1 enhanced the endogenous TRB3 expression level and suppressed its ubiquitination level. These results suggest that APC/C(Cdh1) is involved in ubiquitination and down-regulating the stability of TRB3 protein.
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PMID:Anaphase-promoting complex/cyclosome-cdh1 mediates the ubiquitination and degradation of TRB3. 2006 87

The anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase functions with the E2 ubiquitin-conjugating enzyme UbcH10 in the orderly progression through mitosis by marking key mitotic regulators for destruction by the 26-S proteasome. UbcH10 is overexpressed in many human cancer types and is associated with tumor progression. However, whether UbcH10 overexpression causes tumor formation is unknown. To address this central question and to define the molecular and cellular consequences of UbcH10 overexpression, we generated a series of transgenic mice in which UbcH10 was overexpressed in graded fashion. In this study, we show that UbcH10 overexpression leads to precocious degradation of cyclin B by the APC/C, supernumerary centrioles, lagging chromosomes, and aneuploidy. Importantly, we find that UbcH10 transgenic mice are prone to carcinogen-induced lung tumors and a broad spectrum of spontaneous tumors. Our results identify UbcH10 as a prominent protooncogene that causes whole chromosome instability and tumor formation over a wide gradient of overexpression levels.
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PMID:Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. 2006 91

The APC/C (anaphase-promoting complex/cyclosome) is an E3 ubiquitin ligase that targets specific substrates for degradation by the 26S proteasome. APC/C activity depends on two cofactors, namely Cdc20 (cell division cycle 20) and Cdh1, which select the appropriate targets for ubiquitination. It is well established that APC/C is a target of the SAC (spindle assembly checkpoint) during mitosis and has critical roles in controlling the protein levels of major regulators of mitosis and DNA replication. In addition, recent studies have suggested new cell-cycle-independent functions of APC/C in non-mitotic cells and specifically in neuronal structure and function. Given the relevant functions of APC/C in cell proliferation and neuronal physiology, modulating APC/C activity may have beneficial effects in the clinic.
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PMID:The anaphase-promoting complex/cyclosome (APC/C): cell-cycle-dependent and -independent functions. 2007 37


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