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)

For successful mitosis, Cyclin B1 and Securin must be degraded efficiently before anaphase. Destruction of these mitotic regulators by the 26S proteasome is the result of their poly-ubiquitination by a multi-subunit E3 ligase: the Anaphase-Promoting Complex or Cyclosome (APC/C). Clearly, the APC/C is not just important for mitosis. Destruction of APC/C substrates such as Cdc20, Plk1, Aurora A and Skp2 directs events in G1. Strikingly, the APC/C needs to stay active even in quiescent cells to keep them out of the cell cycle and forms an intriguing link with pRb. An inactive APC/C stabilizes Geminin, Cyclin A and Cyclin B1, thereby securing completion of DNA synthesis and progression through G2-phase. In prometaphase the APC/C becomes active again, but is controlled by the spindle assembly checkpoint. Here we discuss how the APC/C is either held in check or released. We argue that shedding more light on the APC/C is also important to understand cancer and could help the design of treatment.
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PMID:To cell cycle, swing the APC/C. 1854 49

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 mitotic (or spindle assembly) checkpoint system ensures accurate segregation of chromosomes by delaying anaphase until all chromosomes are correctly attached to the mitotic spindle. This system acts by inhibiting the activity of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase to target securin for degradation. APC/C is inhibited by a mitotic checkpoint complex (MCC) composed of BubR1, Bub3, Mad2, and Cdc20. The molecular mechanisms of the inactivation of the mitotic checkpoint, including the release of APC/C from inhibition, remain obscure. It has been reported that polyubiquitylation by the APC/C is required for the inactivation of the mitotic checkpoint [Reddy SK, Rape M, Margansky WA, Kirschner MW (2007) Nature, 446:921-924]. We confirmed the involvement of polyubiquitylation, but found that another process, which requires ATP cleavage at the beta-gamma position (as opposed to alpha-beta bond scission involved in ubiquitylation), is essential for the release of APC/C from checkpoint inhibition. ATP (beta-gamma) cleavage is required both for the dissociation of MCC components from APC/C and for the disassembly of free MCC, whereas polyubiquitylation is involved only in the former process. We find that the requirement for ATP (beta-gamma) cleavage is not due to the involvement of the 26S proteasome and that the phenomena observed are not due to sustained activity of protein kinase Cdk1/cyclin B, caused by inhibition of the degradation of cyclin B. Thus, some other energy-consuming process is needed for the inactivation of the mitotic checkpoint.
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PMID:ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint. 2021 61

The anaphase-promoting complex or cyclosome (APC/C) initiates mitotic exit by ubiquitylating cell-cycle regulators such as cyclin B1 and securin. Lys 48-linked ubiquitin chains represent the canonical signal targeting proteins for degradation by the proteasome, but they are not required for the degradation of cyclin B1. Lys 11-linked ubiquitin chains have been implicated in degradation of APC/C substrates, but the Lys 11-chain-forming E2 UBE2S is not essential for mitotic exit, raising questions about the nature of the ubiquitin signal that targets APC/C substrates for degradation. Here we demonstrate that multiple monoubiquitylation of cyclin B1, catalysed by UBCH10 or UBC4/5, is sufficient to target cyclin B1 for destruction by the proteasome. When the number of ubiquitylatable lysines in cyclin B1 is restricted, Lys 11-linked ubiquitin polymers elaborated by UBE2S become increasingly important. We therefore explain how a substrate that contains multiple ubiquitin acceptor sites confers flexibility in the requirement for particular E2 enzymes in modulating the rate of ubiquitin-dependent proteolysis.
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PMID:APC/C-mediated multiple monoubiquitylation provides an alternative degradation signal for cyclin B1. 2228

Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.
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PMID:Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells. 2300 Oct 11

Meiosis in oocytes consists of two consecutive asymmetric cell divisions, each completed by the extrusion of one set of chromosomes into a small polar body. First polar body (PBI) extrusion is triggered by the inactivation of cyclin-dependent kinase 1 (CDK1), following the degradation of its regulatory subunit cyclin B1 by the ubiquitin proteasome pathway. The present review covers the sequence of events leading to PBI extrusion, and compares them to the corresponding events in mitotic cell division. The latest findings regarding the contribution of ubiquitin chain topology, separase, securin, cyclin B1, CDK1, Polo-like kinase 1 and mitogen-activated protein kinase kinase 1/2 to the regulation of meiosis are discussed.
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PMID:Molecular participants in regulation of the meiotic cell cycle in mammalian oocytes. 2320 31

Viruses commonly manipulate cell cycle progression to create cellular conditions that are most beneficial to their replication. To accomplish this feat, viruses often target critical cell cycle regulators in order to have maximal effect with minimal input. One such master regulator is the large, multisubunit E3 ubiquitin ligase anaphase-promoting complex (APC) that targets effector proteins for ubiquitination and proteasome degradation. The APC is essential for cells to progress through anaphase, exit from mitosis, and prevent a premature entry into S phase. These far-reaching effects of the APC on the cell cycle are through its ability to target a number of substrates, including securin, cyclin A, cyclin B, thymidine kinase, geminin, and many others. Recent studies have identified several proteins from a number of viruses that can modulate APC activity by different mechanisms, highlighting the potential of the APC in driving viral replication or pathogenesis. Most notably, human cytomegalovirus (HCMV) protein pUL21a was recently identified to disable the APC via a novel mechanism by targeting APC subunits for degradation, both during virus infection and in isolation. Importantly, HCMV lacking both viral APC regulators is significantly attenuated, demonstrating the impact of the APC on a virus infection. Work in this field will likely lead to novel insights into viral replication and pathogenesis and APC function and identify novel antiviral and anticancer targets. Here we review viral mechanisms to regulate the APC, speculate on their roles during infection, and identify questions to be addressed in future studies.
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PMID:Control the host cell cycle: viral regulation of the anaphase-promoting complex. 2376 Feb 46

The ubiquitin-conjugating enzymes 2C (UBE2C) is an integral component of the ubiquitin proteasome system. UBE2C consists of a conserved core domain containing the catalytic Cys residue and an N-terminal extension. The core domain is required for ubiquitin adduct formation by interacting with the ubiquitin-fold domain in the E1 enzyme, and contributes to the E3 enzyme binding. UBE2C N-terminal extension regulates E3 enzyme activity as a part of an intrinsic inhibitory mechanism. UBE2C is required for the destruction of mitotic cyclins and securin, which are essential for spindle assembly checkpoint and mitotic exit. The UBE2C mRNA and/or protein levels are aberrantly increased in many cancer types with poor clinical outcomes. Accumulation of UBE2C stimulates cell proliferation and anchorage-independent growth. UBE2C transgenic mice are prone to develop spontaneous tumors and carcinogen-induced tumor with evidence of chromosome aneuploidy.
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PMID:Ubiquitin-conjugating enzyme E2C: a potential cancer biomarker. 2436 2

Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the proteasome. Because blocking mitotic exit is an effective approach for inducing tumour cell death, the APC/C represents a potential novel target for cancer therapy. APC/C activation in mitosis requires binding of Cdc20 (ref. 5), which forms a co-receptor with the APC/C to recognize substrates containing a destruction box (D-box). Here we demonstrate that we can synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting two protein-protein interactions within the APC/C-Cdc20-substrate ternary complex. We identify a small molecule, called apcin (APC inhibitor), which binds to Cdc20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-Cdc20 complex suggests that apcin occupies the D-box-binding pocket on the side face of the WD40-domain. The ability of apcin to block mitotic exit is synergistically amplified by co-addition of tosyl-l-arginine methyl ester, a small molecule that blocks the APC/C-Cdc20 interaction. This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine.
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PMID:Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. 2515 54

The cysteine protease separase opens the cohesin ring by cleaving its kleisin subunit and is a pivotal cell cycle factor for the transition from metaphase to anaphase. It is inhibited by forming a complex with the chaperone securin, and in vertebrates, also by the Cdk1-cyclin B1 complex. Separase is activated upon the destruction of securin or cyclin B1 by the proteasome, after ubiquitination by the anaphase-promoting complex/cyclosome (APC/C). Here we review recent structures of the active protease segment of Chaetomium thermophilum separase in complex with a substrate-mimic inhibitor and full-length Saccharomyces cerevisiae and Caenorhabditis elegans separase in complex with securin. These structures define the mechanism for substrate recognition and catalysis by separase, and show that securin has extensive contacts with separase, consistent with its chaperone function. They confirm that securin inhibits separase by binding as a pseudo substrate.
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PMID:Structural biology of the separase-securin complex with crucial roles in chromosome segregation. 2945 22


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