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 circadian clock is essential for coordinating the proper phasing of many important cellular processes. Robust cycling of key clock elements is required to maintain strong circadian oscillations of these clock-controlled outputs. Rhythmic expression of the Arabidopsis thaliana F-box protein ZEITLUPE (ZTL) is necessary to sustain a normal circadian period by controlling the proteasome-dependent degradation of a central clock protein, TIMING OF CAB EXPRESSION 1 (TOC1). ZTL messenger RNA is constitutively expressed, but ZTL protein levels oscillate with a threefold change in amplitude through an unknown mechanism. Here we show that GIGANTEA (GI) is essential to establish and sustain oscillations of ZTL by a direct protein-protein interaction. GI, a large plant-specific protein with a previously undefined molecular role, stabilizes ZTL in vivo. Furthermore, the ZTL-GI interaction is strongly and specifically enhanced by blue light, through the amino-terminal flavin-binding LIGHT, OXYGEN OR VOLTAGE (LOV) domain of ZTL. Mutations within this domain greatly diminish ZTL-GI interactions, leading to strongly reduced ZTL levels. Notably, a C82A mutation in the LOV domain, implicated in the flavin-dependent photochemistry, eliminates blue-light-enhanced binding of GI to ZTL. These data establish ZTL as a blue-light photoreceptor, which facilitates its own stability through a blue-light-enhanced GI interaction. Because the regulation of GI transcription is clock-controlled, consequent GI protein cycling confers a post-translational rhythm on ZTL protein. This mechanism of establishing and sustaining robust oscillations of ZTL results in the high-amplitude TOC1 rhythms necessary for proper clock function.
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PMID:ZEITLUPE is a circadian photoreceptor stabilized by GIGANTEA in blue light. 1770 63

ATF4 plays a crucial role in the cellular response to stress and the F-box protein beta-TrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for ATF4 degradation by the proteasome, binds to ATF4, and controls its stability. Association between the two proteins depends on ATF4 phosphorylation of serine residues 219 and 224 present in the context of DpSGXXXpS, which is similar but not identical to the DpSGXXpS motif found in most other substrates of beta-TrCP. We used NMR spectroscopy to analyze the structure of the 23P-ATF4 peptide. The 3D structure of the ligand was determined on the basis of NOESY restraints that provide an hairpin loop structure. In contrast, no ordered structure was observed in the NMR experiments for the nonphosphorylated 23-ATF4 in solution. This structural study provides information, which could be used to study the beta-TrCP receptor-ligand interaction in docking procedure. Docking studies showed that the binding epitope of the ligand, is represented by the DpSGIXXpSXE motif. 23P-ATF4 peptide fits the binding pocket of protein beta-TrCP very well, considering that the DpSGIXXpSXE motif adopts an S-turning conformation contrary to the extended DpSGXXpS motif in the other known beta-TrCP ligands.
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PMID:Phosphorylation-dependent structure of ATF4 peptides derived from a human ATF4 protein, a member of the family of transcription factors. 1799 32

The cyclin-dependent kinase inhibitor p27(Kip1) is degraded in late G(1) phase by the ubiquitin-proteasome pathway, allowing cells to enter S phase. Due to accelerated degradation of p27(Kip1), various human cancers express low levels of p27(Kip1) associated with poor prognosis. S-phase kinase-associated protein 2, the F-box protein component of an SCF ubiquitin ligase complex, is implicated in degradation of p27(Kip1) during S-G(2) phases. Recently, Kip1 ubiquitination-promoting complex has been reported as another ubiquitin ligase that targets cytoplasmic p27(Kip1) exported from the nucleus in G(0)-G(1) phases. Here, we identified a RING-H2-type ubiquitin ligase, Pirh2, as a p27(Kip1)-interacting protein. Endogenous Pirh2 physically interacted with endogenous p27(Kip1) in mammalian cells. Pirh2 directly ubiquitinated p27(Kip1) in an intact RING finger domain-dependent manner in vivo, as well as in vitro. Ablation of endogenous Pirh2 by small interfering RNA increased the steady-state level of p27(Kip1) and decelerated p27(Kip1) turnover. Depletion of Pirh2 induced accumulation of p27(Kip1) in both the nucleus and cytoplasm. Pirh2 expression was induced from late G(1)-S phase, whereas p27(Kip1) was decreased in synchronization with accumulation of Pirh2. Furthermore, reduction of Pirh2 resulted in an impairment of p27(Kip1) degradation and an inhibition of cell cycle progression at G(1)-S transition in a p53-independent manner. Overall, the results indicate that Pirh2 acts as a negative regulator of p27(Kip1) function by promoting ubiquitin-dependent proteasomal degradation.
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PMID:Pirh2 promotes ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1. 1800 23

Coordination between cell division and cell differentiation is crucial for growth and development of eukaryotic organisms. Progression through the different phases of cell division requires the specific degradation of proteins through the ubiquitin/proteasome 26S (Ub/26S) pathway. In plants, this pathway plays a key role in controlling several developmental processes and responses, including cell proliferation. SKP2A, an F-box protein, regulates the stability of the cell division E2FC-DPB transcription factor. Here, we show that the SKP2A forms a Skp, Cullin containing (SCF) complexin vivo that has E3 ubiquitin ligase activity. Interestingly, SKP2A is degraded through the Ub/26S pathway, and auxin regulates such degradation. SKP2A positively regulates cell division, at least in part by degrading the E2FC/DPB transcription repressor. Plants that overexpress SKP2A increase the number of cells in G2/M, reduce the level of ploidy and develop a higher number of lateral root primordia. Taken together, our results indicate that SKP2A is a positive regulator of cell division, and its stability is controlled by auxin-dependent degradation.
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PMID:SKP2A, an F-box protein that regulates cell division, is degraded via the ubiquitin pathway. 1803 2

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

Plants flower in response to both environmental and endogenous signals. The Arabidopsis LEAFY (LFY) transcription factor is crucial in integrating these signals, and acts in part by activating the expression of multiple floral homeotic genes. LFY-dependent activation of the homeotic APETALA3 (AP3) gene requires the activity of UNUSUAL FLORAL ORGANS (UFO), an F-box component of an SCF ubiquitin ligase, yet how this regulation is effected has remained unclear. Here, we show that UFO physically interacts with LFY both in vitro and in vivo, and this interaction is necessary to recruit UFO to the AP3 promoter. Furthermore, a transcriptional repressor domain fused to UFO reduces endogenous LFY activity in plants, supporting the idea that UFO acts as part of a transcriptional complex at the AP3 promoter. Moreover, chemical or genetic disruption of proteasome activity compromises LFY-dependent AP3 activation, indicating that protein degradation is required to promote LFY activity. These results define an unexpected role for an F-box protein in functioning as a DNA-associated transcriptional co-factor in regulating floral homeotic gene expression. These results suggest a novel mechanism for promoting flower development via protein degradation and concomitant activation of the LFY transcription factor. This mechanism may be widely conserved, as homologs of UFO and LFY have been identified in a wide array of plant species.
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PMID:An Arabidopsis F-box protein acts as a transcriptional co-factor to regulate floral development. 1828 1

The mitochondrion is a dynamic membranous network whose morphology is conditioned by the equilibrium between ongoing fusion and fission of mitochondrial membranes. In the budding yeast, Saccharomyces cerevisiae, the transmembrane GTPase Fzo1p controls fusion of mitochondrial outer membranes. Deletion or overexpression of Fzo1p have both been shown to alter the mitochondrial fusion process indicating that maintenance of steady-state levels of Fzo1p are required for efficient mitochondrial fusion. Cellular levels of Fzo1p are regulated through degradation of Fzo1p by the F-box protein Mdm30p. How Mdm30p promotes degradation of Fzo1p is currently unknown. We have now determined that during vegetative growth Mdm30p mediates ubiquitylation of Fzo1p and that degradation of Fzo1p is an ubiquitin-proteasome-dependent process. In vivo, Mdm30p associates through its F-box motif with other core components of Skp1-Cullin-F-box (SCF) ubiquitin ligases. We show that the resulting SCF(Mdm30p) ligase promotes ubiquitylation of Fzo1p at mitochondria and its subsequent degradation by the 26S proteasome. These results provide the first demonstration that a cytosolic ubiquitin ligase targets a critical regulatory molecule at the mitochondrial outer membrane. This study provides a framework for developing an understanding of the function of Mdm30p-mediated Fzo1p degradation in the multistep process of mitochondrial fusion.
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PMID:Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion. 1835 67

S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC.
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PMID:Bortezomib (Velcade) induces p27Kip1 expression through S-phase kinase protein 2 degradation in colorectal cancer. 1845 Nov 65

A change in the protein level of RCAN1 (DSCR1/MCIP/Adapt78/CSP1) has been implicated in oxidative stress-induced cell death in neurons and in the pathogenesis of Alzheimer's disease. The pathogenic processes in neurodegenerative diseases are closely related to oxidative stress and the ubiquitin proteasome system (UPS). Therefore, we investigated whether oxidative stress induces a change in the protein level of RCAN1 through the UPS. H2O2 induced ubiquitination of RCAN1 at the same concentrations as those causing a decrease in RCAN1 in HEK293T cells. beta-TrCP, the F-box protein component of SCF ubiquitin ligase, interacted with RCAN1 in response to H2O2 stimulation. Although FBW4, another F-box protein, interacted with RCAN1, its interaction was independent of H2O2 stimulation. In vitro ubiquitination assay showed that SCFbeta-TrCP but not SCFFBW4 increased ubiquitination of RCAN1, dependent on H2O2 stimulation. In addition, knockdown of beta-TrCP by siRNA abolished the H2O2-induced decrease in RCAN1 in HEK293T cells. We further examined whether RCAN1 undergoes ubiquitination by H2O2 in primary neurons, similarly to that in HEK293T cells. An H2O2-induced decrease in RCAN1 was exhibited also in hippocampal and cortical neurons. Ubiquitination of RCAN1 was induced by 500 muM H2O2, the concentration at which H2O2 induced a decrease in RCAN1 in primary neurons. These results suggest that H2O2 induces SCF beta-TrCP-mediated ubiquitination of RCAN1, leading to a decrease in the protein level of RCAN1.
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PMID:Oxidative stress-induced ubiquitination of RCAN1 mediated by SCFbeta-TrCP ubiquitin ligase. 1857 81

Mutations leading to aberrant cytoplasmic localization of nucleophosmin (NPM) are the most frequent genetic alteration in acute myelogenous leukemia (AML). NPM binds the Arf tumor suppressor and protects it from degradation. The AML-associated NPM mutant (NPMmut) also binds p19Arf but is unable to protect it from degradation, which suggests that inactivation of p19Arf contributes to leukemogenesis in AMLs. We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7gamma, a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabilization of Fbw7gamma. As a consequence, c-Myc was stabilized in cells lacking NPM. Expression of NPMmut also led to c-Myc stabilization because of its ability to interact with Fbw7gamma and delocalize it to the cytoplasm, where it is degraded. Because Fbw7 induces degradation of other growth-promoting proteins, the NPM-Fbw7 interaction emerges as a central tumor suppressor mechanism in human cancer.
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PMID:Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma. 1862 39


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