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 recently identified centrosome protein Nlp (ninein-like protein) is a key regulator in centrosome maturation, which contributes to chromosome segregation and cytokinesis. However, the mechanism(s) controlling Nlp expression remains largely unknown. Here we have shown that Nlp expression is cell cycle-dependent with a peak at G(2)/M transition in human cells. Nlp is a short-lived protein and degraded by the proteasome via the anaphase-promoting cyclosome complex (APC/c) pathway. It interacts with the APC/c through the APC2 or Cdc27 subunits and is ubiquitinated. Following treatment with proteasome inhibitors, its protein level is elevated. Nlp binds in vivo to the degradation-targeting proteins Cdh1 and Cdc20, and overexpression of Cdh1 and Cdc20 enhances Nlp degradation. Using point mutations of the two putative degradation signals in Nlp, we have found that its degradation requires intact KEN-box and D-box. Interestingly, the Lys-Glu-Asn-D-box-mutated Nlp exhibits a much stronger capability of inducing anchorage-independent growth and multinuclearity compared with the wild type Nlp. Taken together, these findings indicate that Nlp expression is cell cycle-dependent and regulated by APC-mediated protein degradation.
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PMID:Cell cycle-dependent expression of centrosomal ninein-like protein in human cells is regulated by the anaphase-promoting complex. 1740 70

Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
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PMID:Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. 1748 76

Mounting evidence suggests that dynamic interactions between a tumor and its microenvironment play a critical role in tumor development, cell-cycle progression, and response to therapy. In this study, we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stromal cells resulted in a reversible G(1) arrest associated with elevated p27(Kip1) and p21 (WAF1) proteins. The adhesion-mediated p27(Kip1) and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCF(Skp2) ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27(Kip1), whereas inhibition of Skp2 by siRNA increased p27(Kip1) and p21 levels. Furthermore, we found cell adhesion up-regulated Cdh1 (an activating subunit of anaphase-promoting complex [APC] ubiquitin ligase), and reduction of Cdh1 by siRNA induced Skp2 accumulation and hence p27(Kip1) degradation, thus implicating Cdh1 as an upstream effector of the Skp2/p27(Kip1) signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls the tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHLs. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy.
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PMID:Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. 1750 56

CD8 T cells resolve intracellular pathogens by responding to pathogen-derived peptides that are presented on the cell surface by MHC class I molecules. Although most pathogens encode a large variety of antigenic peptides, protective CD8 T cell responses target usually only a few of these. To determine the mechanism by which the IFN-gamma-inducible proteasome (immuno) subunits enhance the ability of specific pathogen-derived peptides to elicit CD8 T cell responses, we generated a recombinant Listeria monocytogenes strain (rLM-E1) that secretes a model Ag encompassing the immunoproteasome-dependent E1B(192-200) and immunoproteasome-independent E1A(234-243) epitope. Analyses of Ag presentation showed that infected gene-deficient professional APCs, lacking the immunosubunits LMP7/ibeta5 and MECL-1/ibeta2, processed and presented the rLM-E1-derived E1B(192-200) epitope but with delayed kinetics. E1A epitope processing proceeded normally in these cells. Accordingly, infected gene-deficient mice failed to respond to the otherwise immunodominant E1B(192-200) epitope but mounted normal CD8 T cell responses to E1A(234-243) which was processed by the same professional APCs, from the same rLM-E1 Ag. The inability of gene-deficient mice to respond to E1B(192-200) was not explained by insufficient quantities of antigenic peptide, as splenic APC of 36-h-infected gene-deficient mice that presented the two E1 epitopes at steady state levels elicited responses to both E1B(192-200) and E1A(234-243) when transferred into LMP7+MECL-1-deficient mice. Taken together, our findings indicate that not absolute epitope quantities but early Ag-processing kinetics determine the ability of pathogen-derived peptides to elicit CD8 T cell responses, which is of importance for rational T cell vaccine design.
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PMID:Rates of processing determine the immunogenicity of immunoproteasome-generated epitopes. 1754 90

Ubiquitin-dependent proteolysis plays an important role in regulating fundamental biological functions, including cell division and cellular differentiation. Previous studies implicate the ubiquitin-proteasome system (UPS) in myogenic differentiation through regulating cell cycle progression and modulating myogenic factors such as MyoD and Myf5. Certain ubiquitin protein ligases, including the SCF complex and APC, have been suggested to govern terminal muscle differentiation. However, the underlying mechanism of regulation of both the cell cycle and myogenic factors by the UPS during this process remains unclear. We have dissected the role of the UPS in myogenic differentiation using an in vitro muscle differentiation system based on C2C12 cells. We demonstrate that Cdh1-APC regulates two critical proteins, Skp2 and Myf5, for proteolysis during muscle differentiation. The targeting of Skp2 by Cdh1-APC for destruction results in elevation of p21 and p27, which are crucial for coordinating cellular division and differentiation. Degradation of Myf5 by Cdh1-APC facilitates myogenic fusion. Knockdown of Cdh1 by siRNA significantly attenuates muscle differentiation. Taken together, Cdh1-APC is an important ubiquitin E3 ligase that modulates muscle differentiation through coordinating cell cycle progression and initiating the myogenic differentiation program.
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PMID:The dual effects of Cdh1/APC in myogenesis. 1760 83

Proteolytic destruction of many cyclins is induced by a multi-subunit ubiquitin ligase termed the anaphase promoting complex/cyclosome (APC/C). In the budding yeast Saccharomyces cerevisiae, the S phase cyclin Clb5 and the mitotic cyclins Clb1-4 are known as substrates of this complex. The relevance of APC/C in proteolysis of Clb5 is still under debate. Importantly, a deletion of the Clb5 destruction box has little influence on cell cycle progression. To understand Clb5 degradation in more detail, we applied in vivo pulse labeling to determine the half-life of Clb5 at different cell cycle stages and in the presence or absence of APC/C activity. Clb5 is significantly unstable, with a half-life of approximately 8-10 min, at cell cycle periods when APC/C is inactive and in mutants impaired in APC/C function. A Clb5 version lacking its cyclin destruction box is similarly unstable. The half-life of Clb5 is further decreased in a destruction box-dependent manner to 3-5 min in mitotic or G(1) cells with active APC/C. Clb5 instability is highly dependent on the function of the proteasome. We conclude that Clb5 proteolysis involves two different modes for targeting of Clb5 to the proteasome, an APC/C-dependent and an APC/C-independent mechanism. These different modes apparently have overlapping functions in restricting Clb5 levels in a normal cell cycle, but APC/C function is essential in the presence of abnormally high Clb5 levels.
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PMID:A process independent of the anaphase-promoting complex contributes to instability of the yeast S phase cyclin Clb5. 1762 Mar 41

Centrosome duplication involves the formation of a single procentriole next to each centriole, once per cell cycle. The mechanisms governing procentriole formation and those restricting its occurrence to one event per centriole are poorly understood. Here, we show that HsSAS-6 is necessary for procentriole formation and that it localizes asymmetrically next to the centriole at the onset of procentriole formation. HsSAS-6 levels oscillate during the cell cycle, with the protein being degraded in mitosis and starting to accumulate again at the end of the following G1. Our findings indicate that APC(Cdh1) targets HsSAS-6 for degradation by the 26S proteasome. Importantly, we demonstrate that increased HsSAS-6 levels promote formation of more than one procentriole per centriole. Therefore, regulated HsSAS-6 levels normally ensure that each centriole seeds the formation of a single procentriole per cell cycle, thus playing a fundamental role in driving the centrosome duplication cycle and ensuring genome integrity.
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PMID:Regulated HsSAS-6 levels ensure formation of a single procentriole per centriole during the centrosome duplication cycle. 1768 Nov 32

Human chromosome 11q23 translocations disrupting MLL result in poor prognostic leukemias. It fuses the common MLL N-terminal approximately 1400 amino acids in-frame with >60 different partners without shared characteristics. In addition to the well-characterized activity of MLL in maintaining Hox gene expression, our recent studies established an MLL-E2F axis in orchestrating core cell cycle gene expression including Cyclins. Here, we demonstrate a biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCF(Skp2) and APC(Cdc20) mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M-phase progression. Conversely, overexpression of MLL blocks S-phase progression. Remarkably, MLL degradation initiates at its N-terminal approximately 1400 amino acids, and tested prevalent MLL fusions are resistant to degradation. Thus, impaired degradation of MLL fusions likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) assures the temporal necessity of MLL in coordinating cell cycle progression.
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PMID:Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. 1790 26

Cellular transition to anaphase and mitotic exit has been linked to the loss of cyclin-dependent kinase 1 (Cdk1) kinase activity as a result of anaphase-promoting complex/cyclosome (APC/C)-dependent specific degradation of its cyclin B1 subunit. Cdk1 inhibition by roscovitine is known to induce premature mitotic exit, whereas inhibition of the APC/C-dependent degradation of cyclin B1 by MG132 induces mitotic arrest. In this study, we find that combining both drugs causes prolonged mitotic arrest in the absence of Cdk1 activity. Different Cdk1 and proteasome inhibitors produce similar results, indicating that the effect is not drug specific. We verify mitotic status by the retention of mitosis-specific markers and Cdk1 phosphorylation substrates, although cells can undergo late mitotic furrowing while still in mitosis. Overall, we conclude that continuous Cdk1 activity is not essential to maintain the mitotic state and that phosphatase activity directed at Cdk1 substrates is largely quiescent during mitosis. Furthermore, the degradation of a protein other than cyclin B1 is essential to activate a phosphatase that, in turn, enables mitotic exit.
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PMID:Mitosis persists in the absence of Cdk1 activity when proteolysis or protein phosphatase activity is suppressed. 1802 3

Recently, the ubiquitin proteasome system (UPS) has matured as a drug discovery arena, largely on the strength of the proven clinical activity of the proteasome inhibitor Velcade in multiple myeloma. Ubiquitin ligases tag cellular proteins, such as oncogenes and tumor suppressors, with ubiquitin. Once tagged, these proteins are degraded by the proteasome. The specificity of this degradation system for particular substrates lies with the E3 component of the ubiquitin ligase system (ubiquitin is transferred from an E1 enzyme to an E2 enzyme and finally, thanks to an E3 enzyme, directly to a specific substrate). The clinical effectiveness of Velcade (as it theoretically should inhibit the output of all ubiquitin ligases active in the cell simultaneously) suggests that modulating specific ubiquitin ligases could result in an even better therapeutic ratio. At present, the only ubiquitin ligase leads that have been reported inhibit the degradation of p53 by Mdm2, but these have not yet been developed into clinical therapeutics. In this review, we discuss the biological rationale, assays, genomics, proteomics and three-dimensional structures pertaining to key targets within the UPS (SCFSkp2 and APC/C) in order to assess their drug development potential. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
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PMID:Wrenches in the works: drug discovery targeting the SCF ubiquitin ligase and APC/C complexes. 1804 46


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