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)

Lens fiber cell differentiation involves extensive reconstruction of the cell's architecture, including the degradation and elimination of all membrane-bound organelles via a process that has been likened to apoptosis. Using caspase reporter assays under conditions in which nonspecific cleavage of the reporter peptides by the proteasome has been inhibited, we investigated whether any specific caspase activities are temporally correlated with this process of organelle loss. Extracts from neonatal mouse lenses contained strong VEID-7-amino-4-trifluoromethylcoumarin (AFC) and minor IETD-AFC and LEVD-AFC cleavage activities, but no DEVD-AFC cleavage activity. Further testing suggested that the VEID-AFC and IETD-AFC cleavage activities were likely due to the same enzyme. In lens extracts from rat embryos, VEID-AFC cleavage activity increased during the period when organelles are eliminated, between embryonic days 15.5 and 18.5, whereas procaspase-6 protein levels decreased, suggesting that this enzyme is responsible for VEID-AFC cleavage. By contrast, in extracts from alpha AE7 transgenic mouse lenses in which apoptosis was induced, strong DEVD-AFC cleavage activity and activated caspase-3 protein were detected. Thus, within the same tissue, different caspase activities can predominate depending on the context, normal differentiation versus apoptosis. These results highlight the difference between normal fiber cell differentiation and apoptosis and the capacity of the lens to differentially regulate these two processes.
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PMID:Temporal regulation of VEID-7-amino-4-trifluoromethylcoumarin cleavage activity and caspase-6 correlates with organelle loss during lens development. 1516 22

Saccharomyces cerevisiae cells possess a plasma membrane sensor able to detect the presence of extracellular amino acids and then to activate a signaling pathway leading to transcriptional induction of multiple genes, e.g., AGP1, encoding an amino acid permease. This sensing function requires the permease-like Ssy1 and associated Ptr3 and Ssy5 proteins, all essential to activation, by endoproteolytic processing, of the membrane-bound Stp1 transcription factor. The SCF(Grr1) ubiquitin-ligase complex is also essential to AGP1 induction, but its exact role in the amino acid signaling pathway remains unclear. Here we show that Stp1 undergoes casein kinase I-dependent phosphorylation. In the yck mutant lacking this kinase, Stp1 is not cleaved and AGP1 is not induced in response to amino acids. Furthermore, we provide evidence that Ssy5 is the endoprotease responsible for Stp1 processing. Ssy5 is significantly similar to serine proteases, its self-processing is a prerequisite for Stp1 cleavage, and its overexpression causes inducer-independent Stp1 cleavage and high-level AGP1 transcription. We further show that Stp1 processing also requires the SCF(Grr1) complex but is insensitive to proteasome inhibition. However, Stp1 processing does not require SCF(Grr1), Ssy1, or Ptr3 when Ssy5 is overproduced. Finally, we describe the properties of a particular ptr3 mutant that suggest that Ptr3 acts with Ssy1 in amino acid detection and signal initiation. We propose that Ssy1 and Ptr3 form the core components of the amino acid sensor. Upon detection of external amino acids, Ssy1-Ptr3 likely allows-in a manner dependent on SCF(Grr1)-the Ssy5 endoprotease to gain access to and to cleave Stp1, this requiring prior phosphorylation of Stp1 by casein kinase I.
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PMID:Amino acid signaling in yeast: casein kinase I and the Ssy5 endoprotease are key determinants of endoproteolytic activation of the membrane-bound Stp1 transcription factor. 1550 82

We undertook a growth-based screen exploiting the degradation of CTL*, a chimeric membrane-bound ERAD substrate derived from soluble lumenal CPY*. We screened the Saccharomyces cerevisiae genomic deletion library containing approximately 5000 viable strains for mutants defective in endoplasmic reticulum (ER) protein quality control and degradation (ERAD). Among the new gene products we identified Yos9p, an ER-localized protein previously involved in the processing of GPI anchored proteins. We show that deficiency in Yos9p affects the degradation only of glycosylated ERAD substrates. Degradation of non-glycosylated substrates is not affected in cells lacking Yos9p. We propose that Yos9p is a lectin or lectin-like protein involved in the quality control of N-glycosylated proteins. It may act sequentially or in concert with the ERAD lectin Htm1p/Mnl1p (EDEM) to prevent secretion of malfolded glycosylated proteins and deliver them to the cytosolic ubiquitin-proteasome machinery for elimination.
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PMID:A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. 1555 21

Lipofuscin is membrane-bound cellular waste that can be neither degraded nor ejected from the cell but can only be diluted through cell division and subsequent growth. The fate of postmitotic cells is to accumulate lipofuscin, which as an "aging pigment" has been considered a reliable biomarker for the age of cells such as neurons and, by extension, their hosts. In the aging human brain, deposits of lipofuscin are not uniformly distributed but are concentrated in specific regions of functional interest. The prevailing thought is that the major source of lipofuscin is incomplete lysosomal degradation of damaged mitochondria. Accumulating evidence suggests that lipofuscin is not benign but can impair the functioning of seemingly unrelated cellular systems, including the ubiquitin/proteasome pathway. A damaging feedback loop of lysosomal and proteasomal inhibition may occur as lipofuscin accumulates, leading to what has been appropriately named a "garbage catastrophe." Reversing this catastrophe presents a formidable challenge.
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PMID:Lipofuscin and aging: a matter of toxic waste. 1568 3

STRA13 is a hypoxia-inducible bHLH transcription factor implicated in the pVHL/HIF, TGF-beta, and Jak/STAT pathways. To further characterize the STRA13 protein-interacting network and mechanisms of STRA13-dependent transcription, we utilized yeast two-hybrid screening. Here we report on STRA13 interaction with the cell cycle-associated transcription factor MSP58. We demonstrated that the basic domain of STRA13 and the FHA domain of MSP58 are essential for this association. We performed phospho-peptide mapping of both MSP58 and STRA13 and showed that their association was modulated by the STRA13 phosphorylation status. STRA13/MSP58 complex formation protected both proteins from the proteasome-mediated degradation, extending their half-lives considerably. STRA13 and MSP58 synergistically co-operated in the STRA13 promoter-driven transcription repression. Both proteins were co-localized in the nucleus and showed transcript accumulation during the S phase of the cell cycle. Thus, we characterize a novel STRA13-associated transcription repression complex and provide a link between cell cycle regulation and STRA13 activity.
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PMID:Association, mutual stabilization, and transcriptional activity of the STRA13 and MSP58 proteins. 1571 73

Neuronal intranuclear inclusion disease (NIID) is reported in a 16-year-old Pure Spanish breed female horse suffering from progressive ataxia and motor deficiencies. The neuropathological study revealed NIIs throughout the central nervous system, although mainly in the brain stem and spinal cord. This distribution did not correlate with neuron loss, which was marked in the hippocampus and moderate in the neocortex, particularly in the occipital cortex. As in humans, NIIs in the horse were hyaline autofluorescent inclusions composed of non-membrane-bound aggregates of filaments and fine granules. NIIs were stained with anti-ubiquitin and anti-clusterin antibodies. In addition, NIIs were stained with antibodies raised against subunits of the 19S and PA28, but not of the 20S, components of the proteasome. These observations indicate similarities between NIID in humans and horses, and suggest that clusterin and abnormal ubiquitin-proteasomal expression participate in NII formation.
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PMID:Neuronal intranuclear inclusion disease in a horse. 1597 Oct 54

Dendritic cells are professional antigen-presenting cells associated with efficient antigen processing and presentation to T cells. However, recent evidence also suggests that dendritic cells may mediate direct tumoricidal functions. In this study, we investigated the mechanism by which murine dendritic cells mediate the apoptotic death of murine lymphoma cell lines, and whether dendritic cell effector function could be enhanced by preconditioning tumor cells with the protein phosphatase inhibitor nitric oxide (NO) by altering the balance of proapoptotic/antiapoptotic proteins in the treated cells. We observed that NO donor compound sensitized lymphomas to dendritic cell-mediated cytotoxicity in vitro. Both immature and spontaneously matured bone marrow-derived dendritic cells (SM-DC) were capable of inducing tumor cell apoptosis, with SM-DCs serving as comparatively better killers. Fas ligand (FasL)-Fas engagement proved important in this activity because elevated expression of membrane-bound FasL was detected on SM-DCs, and dendritic cells derived from FasL-deficient mice were less capable of killing NO-sensitized tumor cells than wild-type dendritic cells. As FasL-deficient dendritic cells were still capable of mediating a residual degree of tumor killing, this suggests that FasL-independent mechanisms of apoptosis are also involved in dendritic cell-mediated tumor killing. Because NO-treated tumor cells displayed a preferential loss of survivin protein expression via a proteasome-dependent pathway, enhanced tumor sensitivity to dendritic cell-mediated killing may be associated with the accelerated turnover of this critical antiapoptotic gene product. Importantly, NO-treated tumor cells were also engulfed more readily than control tumor cells and this resulted in enhanced cross-presentation of tumor-associated antigens to specific T cells in vitro.
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PMID:Nitric oxide sensitizes tumor cells to dendritic cell-mediated apoptosis, uptake, and cross-presentation. 1616 26

Endoplasmic reticulum (ER)-associated protein degradation requires the dislocation of selected substrates from the ER to the cytosol for proteolysis via the ubiquitin-proteasome system. The AAA ATPase Cdc48 (known as p97 or VCP in mammals) has a crucial, but poorly understood role in this transport step. Here, we show that Ubx2 (Sel1) mediates interaction of the Cdc48 complex with the ER membrane-bound ubiquitin ligases Hrd1 (Der3) and Doa10. The membrane protein Ubx2 contains a UBX domain that interacts with Cdc48 and an additional UBA domain. Absence of Ubx2 abrogates breakdown of ER proteins but also that of a cytosolic protein, which is ubiquitinated by Doa10. Intriguingly, our results suggest that recruitment of Cdc48 by Ubx2 is essential for turnover of both ER and non-ER substrates, whereas the UBA domain of Ubx2 is specifically required for ER proteins only. Thus, a complex comprising the AAA ATPase, a ubiquitin ligase and the recruitment factor Ubx2 has a central role in ER-associated proteolysis.
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PMID:Ubx2 links the Cdc48 complex to ER-associated protein degradation. 1617 53

Alcohol-inducible cytochrome P450 2E1 (CYP2E1) has the most rapid turnover of any member of this large family of membrane-bound oxygenases, and its degradation rate is altered profoundly by various substrates, such as ethanol and CCl(4). CYP2E1 is degraded by the ubiquitin-proteasome pathway, and because the hsp90/hsp70-based chaperone machinery is often involved in maintaining the balance between protein integrity and degradation by this pathway, we have asked whether CYP2E1 is regulated by the chaperone machinery. We show here that treatment of transformed human skin fibroblasts stably expressing CYP2E1 with the hsp90 inhibitor radicicol results in CYP2E1 degradation that is inhibited by the proteasome inhibitor lactacystin. Immunoadsorption of hsp90 from cytosol of HEK cells expressing the truncated CYP2E1(Delta3-29) yields coadsorption of CYP2E1(Delta3-29). Cotransfection of HEK cells with both the truncated CYP2E1 and the hsp70-dependent E3 ubiquitin ligase CHIP results in CYP2E1(Delta3-29) degradation, and CYP2E1(Delta3-29) co-immunoadsorbs with myc-CHIP from cytosol of cotransfected cells. Purified, bacterially expressed CYP2E1(Delta3-29) is ubiquitylated in a CHIP-dependent manner when it is incubated with a purified system containing the E1 ubiquitin activating enzyme, E2, and CHIP. CYP2E1 is the first P450 shown to be an hsp90 "client" protein that can be ubiquitylated by the hsp70-dependent E3 ubiquitin ligase CHIP. Our observations lead to a general model of how substrates, such as ethanol, can regulate the interaction of CYP2E1 with the chaperones hsp90 and hsp70 to profoundly alter enzyme turnover.
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PMID:Regulation of cytochrome P450 2E1 by heat shock protein 90-dependent stabilization and CHIP-dependent proteasomal degradation. 1633 94

The activity of a set of peptidases (proteases) involved in cancer progression is collectively known as the cancer 'degradome'. Invasion and metastasis were initially considered as late events in cancer development and the processes in which proteases were involved. However, recent studies indicate that invasion and metastasis are not late events, but can occur during early stages as well. Moreover, other processes occurring in various stages of cancer progression are also protease-dependent, such as (upregulation of) cell proliferation, (downregulation of) apoptosis, involvement of white blood cells, angiogenesis and induction of multi-drug resistance. Proteolytic activity in tumours is regulated in a complex manner, as both genetically unstable cancer cells and stable stromal cells, such as fibroblasts, endothelial cells and inflammatory cells, are involved. In vitro studies and studies using animal models have clearly shown protease dependency of many processes in carcinogenesis. However, clinical trials using protease inhibitors have thus far been unsuccessful except for a few applications of matrix metalloprotease (MMP) inhibitors when used in combination with cytostatic anticancer agents and/or in the early stages of cancer. Antithrombotics, such as low-molecular-weight heparin and warfarin, were also successful in clinical trials, probably by interfering with proteases of the coagulation cascade. The two-way association between cancer and thrombosis has long been recognised in the clinic. The poor outcome of other clinical trials of protease inhibitors is probably due to the late stages of cancer of the patient populations included, and the limited understanding of the complex regulation and effects of the activity of the various proteases in tumours depending on, among others, tumour type and stage, interactions between the cancer cells, other cells and the extracellular matrix in tumours. Therefore, a better fundamental understanding of the proteolytic complexity in tumours is essential before clinical trials can be rationally designed. At present, antithrombotics, the urokinase-type plasminogen activator system, the membrane-bound membrane-type 1-MMP, cathepsin L and the proteasome seem the most promising candidates as targets for anticancer strategies in early stages of cancer in combination with cytotoxic drugs. Moreover, metronomic therapy is an attractive approach using low doses of inhibitors for prolonged periods of time without interruption to specifically target endothelial cells that are involved in angiogenesis.
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PMID:Antiprotease therapy in cancer: hot or not? 1650 35


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