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 p53 tumor suppressor is activated by many diverse stress signals through mechanisms that result in stabilization and accumulation of the p53 protein. p53 is normally degraded through the proteasome following interaction with MDM2, which both functions as a ubiquitin ligase for p53 and shuttles to the cytoplasm, where p53 degradation occurs. Stabilization of p53 in response to stress is associated with inhibition of MDM2-mediated degradation, which has been associated with phosphorylation of p53 in response to DNA damage or activation of ARF. In this study we show distinct responses, as measured by phosphorylation, transcriptional activity, and subcellular localization, of p53 stabilized by different activating signals. Although normal cells and wild-type p53-expressing tumor cells showed similar responses to actinomycin D and camptothecin treatment, the transcriptional activity of stabilized p53 induced by deferoxamine mesylate, which mimics hypoxia, in normal cells was lost in all three tumor cell lines tested. Our results show that multiple pathways exist to stabilize p53 in response to different forms of stress, and they may involve down-regulation of MDM2 expression or regulation of the subcellular localization of p53 or MDM2. Loss of any one of these pathways may predispose cells to malignant transformation, although reactivation of p53 might be achieved through alternative pathways that remain functional in these tumor cells.
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PMID:Stress signals utilize multiple pathways to stabilize p53. 1075 6

The p53 tumour suppressor protein is down-regulated by the action of Mdm2, which targets p53 for rapid degradation by the ubiquitin-proteasome pathway. The p14ARF protein is also a potent tumour suppressor that acts by binding to Mdm2 and blocking Mdm2-dependent p53 degradation and transcriptional silencing. We have screened a series of overlapping synthetic peptides derived from the p14ARF protein sequence and found that a peptide corresponding to the first 20 amino acids of ARF (Peptide 3) could bind human Mdm2. The binding site for Peptide 3 on Mdm2 was determined by deletion mapping and lies adjacent to the binding site of the anti-Mdm2 antibody 2A10, which on microinjection into cells can activate p53-dependent transactivation of a reporter plasmid. To determine whether Peptide 3 could similarly activate p53, we expressed a fusion of green fluorescent protein and Peptide 3 in MCF7 and U-2 OS cells and were able to demonstrate induction of p53 protein and p53-dependent transcription. Peptide 3 was able to block in vitro ubiquitination of p53 mediated by Mdm2. Small peptides which are sufficient to block degradation of p53 could provide therapeutic agents able to restore p53-dependent cell death pathways in tumours that retain wild-type p53 expression.
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PMID:An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. 1082 82

Members of the HERC (domain homologous to E6 associated protein carboxy-terminus and RCC1 domain protein) family may function both as guanine nucleotide exchange factors and E3 ubiquitin ligases. Here we identify an unstudied member, HERC3. This protein was recognized by specific antibodies in different cell types. HERC3 was located in the cytosol and in vesicular-like structures containing beta-COP, ARF and Rab5 proteins. Involvement of HERC3 in the ubiquitin system was suggested by its ability to interact with ubiquitin. The conserved cysteine in HECT proteins was not essential for this non-covalent binding. Moreover, HERC3 was a substrate of ubiquitination being degraded by the proteasome. These observations indicate a fine regulation of HERC3 and suggest a role in vesicular traffic and ubiquitin-dependent processes.
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PMID:HERC3 binding to and regulation by ubiquitin. 1116 99

While the transactivation function of the tumor suppressor p53 is well understood, less is known about the transrepression functions of this protein. We have previously shown that p53 interacts with the corepressor protein mSin3a (hereafter designated Sin3) in vivo and that this interaction is critical for the ability of p53 to repress gene expression. In the present study, we demonstrate that expression of Sin3 results in posttranslational stabilization of both exogenous and endogenous p53, due to an inhibition of proteasome-mediated degradation of this protein. Stabilization of p53 by Sin3 requires the Sin3-binding domain, determined here to map to the proline-rich region of p53, from amino acids 61 to 75. The correlation between Sin3 binding and stabilization supports the hypothesis that this domain of p53 may normally be subject to a destabilizing influence. The finding that a synthetic mutant of p53 lacking the Sin3-binding domain has an increased half-life in cells, compared to wild-type p53, supports this premise. Interestingly, unlike retinoblastoma tumor suppressor protein, MDMX, and p14(ARF), Sin3 stabilizes p53 in an MDM2-independent manner. The ability of Sin3 to stabilize p53 is consistent with the model whereby these two proteins must exist on a promoter for extended periods, in order for repression to be an effective mechanism of gene regulation. This model is consistent with our data indicating that, unlike the p300-p53 complex, the p53-Sin3 complex is immunologically detectable for prolonged periods following exposure of cells to agents of DNA damage.
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PMID:The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation. 1135 5

The tumor suppressor p53 is a labile protein whose level is known to be regulated by the Mdm-2-ubiquitin-proteasome degradation pathway. We have found another pathway for p53 proteasomal degradation regulated by NAD(P)H quinone oxidoreductase 1 (NQO1). Inhibition of NQO1 activity by dicoumarol induces p53 and p73 proteasomal degradation. A mutant p53 (p53([22,23])), which is resistant to Mdm-2-mediated degradation, was susceptible to dicoumarol-induced degradation. This finding indicates that the NQO1-regulated proteasomal p53 degradation is Mdm-2-independent. The tumor suppressor p14(ARF) and the viral oncogenes SV40 LT and adenovirus E1A that are known to stabilize p53 inhibited dicoumarol-induced p53 degradation. Unlike Mdm-2-mediated degradation, the NQO1-regulated p53 degradation pathway was not associated with accumulation of ubiquitin-conjugated p53. In vitro studies indicate that dicoumarol-induced p53 degradation was ubiquitin-independent and ATP-dependent. Inhibition of NQO1 activity in cells with a temperature-sensitive E1 ubiquitin-activating enzyme induced p53 degradation and inhibited apoptosis at the restrictive temperature without ubiquitination. Mdm-2 failed to induce p53 degradation under these conditions. Our results establish a Mdm-2- and ubiquitin-independent mechanism for proteasomal degradation of p53 that is regulated by NQO1. The lack of NQO1 activity that stabilizes a tumor suppressor such as p53 can explain why humans carrying a polymorphic inactive NQO1 are more susceptible to tumor development.
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PMID:Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. 1223 53

The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53. We present evidence that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes. This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM2. Promotion of MDM2-mediated MDMX ubiquitination requires the N-terminal domain of ARF, which normally inhibits MDM2 ubiquitination of p53. An intact RING domain of MDM2 is also required, both to interact with MDMX and to provide E3 ligase function. Increase of MDM2 and ARF levels by DNA damage, recombinant ARF adenovirus infection, or inducible MDM2 expression leads to proteasome-mediated down-regulation of MDMX levels. Therefore, MDMX and MDM2 are coordinately regulated by stress signals. The ARF tumor suppressor differentially regulates the ability of MDM2 to promote p53 and MDMX ubiquitination and activates p53 by targeting both members of the MDM2 family.
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PMID:MDM2 promotes ubiquitination and degradation of MDMX. 1286 Sep 99

The E7 oncoprotein encoded by high-risk types of human papillomavirus (HPV) plays a significant role in the development of HPV-related cancers. E7 is a potent stimulator of S phase and host DNA replication. These functions of E7 are linked to the deregulation of the Rb family of proteins. For example, E7 binds and induces proteolysis of Rb through the ubiquitin-proteasome pathway. Despite advances in our understanding of E7, reagents that inhibit E7 with promise in therapy have not been developed or identified. Here, we provide evidence that the tumor suppressor ARF can inhibit E7. We show that the expression of ARF causes a relocalization of E7 from the nucleoplasm to the nucleolus. Two distinct regions in ARF overlapping with the MDM2-binding sites are necessary for the relocalization of E7. Furthermore, we show that ARF blocks the proteolysis of Rb induced by E7. In addition, ARF expression inhibits DNA replication induced by E7. Although it is not known whether the endogenous ARF, which is expressed at a low level, interferes with E7, our results suggest that ARF is an effective inhibitor of E7. We speculate that ARF or an ARF-derived molecule might have a significant impact in therapy against HPV-related tumors.
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PMID:P19ARF inhibits the functions of the HPV16 E7 oncoprotein. 1293 9

The p14ARF tumor suppressor is a key regulator of cellular proliferation, frequently inactivated in human cancer, whose mode of action is currently not completely understood. We report here that the so-called human immunodeficiency virus Tat-binding protein-1 (TBP-1), a component of the 19 S regulatory subunit of the proteasome 26 S, also involved in transcriptional regulation and with a supposed role in the control of cell proliferation, specifically interacts with ARF, both in yeast and mammalian cells. We present evidence that the overexpression of TBP-1 in various cell lines results in a sharp increase of both transfected and endogenous ARF protein levels. Moreover, this effect depends on the binding between the two proteins and, at least in part, is exerted at the post-translational level. We also show that the ARF increase following TBP-1 overexpression results in an increase in p53 protein levels and activity. Finally, our data underline a clear involvement of TBP-1 in the control of cell proliferation.
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PMID:Functional and physical interaction of the human ARF tumor suppressor with Tat-binding protein-1. 1466 36

Ubiquitin inhibitors act at many levels to enhance apoptosis signaling. For TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis signaling, there are at least five mechanisms by which apoptosis are regulated by the ubiquitin-proteasome pathway. First, proteasome inhibitors can decrease Fas-like inhibitor protein (FLIP) protein levels in tumors, resulting in increased apoptosis signaling due to increased caspase-8 activation. This appears to involve the ubiquitin ligase TNF receptor activation factor-2 (TRAF2) and acts indirectly by causing cell-cycle arrest at a stage where there is high degradation of the FLIP-TRAF2 complex. Second, the regulation of the proapoptotic Bcl-2 family member BAX occurs indirectly. Apoptosis signaling and caspase activation results in a confirmation change in the normally monomeric BAX, which exposes the BH3 domain of BAX, leading to dimerization and resistance to ubiquitin degradation. BAX then translocates into the mitochondria, resulting in the release of proapoptotic mitochondrial factors such as cytochrome c and second mitochondria-derived activator of caspase (SMAC). This results in the activation of caspase-9 and formation of the apoptosome and efficient apoptosis signaling. A third mechanism of the regulation of TRAIL signaling in the ubiquitin-proteasome pathway is mediated by the inhibitor of apoptosis proteins (IAP) E3 ligases. These IAPs can directly bind to caspases but also can act as ubiquitin ligases for caspases, resulting in the degradation of these caspases. IAP binding to caspases can be inhibited by SMAC, which exhibits a caspase-9 homology domain. The fourth mechanism for apoptosis activation by proteasome inhibitors is through the stabilization of the inhibitor of the kappaB (IkappaB)/NF-kappaB complex and prevention of nuclear translocation of the antiapoptosis transcription factor NF-kappaB. During TRAIL-DR4, DR5 signaling, this pathway is activated by interactions of activated Fas-associated death domain with activated receptor-interacting protein (RIP), which in turn activates NF-kappaB-inducing kinase and phosphorylates IkappaB. Therefore, the inhibition of IkappaB degradation blocks this RIP-mediated antiapoptosis signaling event. Last, p53 protein levels, and susceptibility to apoptosis, can be deregulated by the human homolog Hdm2 (Mdm2) E3 ligase. This process is inhibited by p53 phosphorylation and by sequestration of Mdm2 by ARF. Better mechanisms to inhibit the ubiquitin-proteasome pathway targeted at the ubiquitin-proteasome degradation process itself, or more specifically at the E3 ligases known to modulate and downregulate proapoptosis pathways will lead to the enhancement of TRAIL apoptosis signaling and better cancer therapeutic outcomes act through this pathway.
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PMID:Regulation of apoptosis proteins in cancer cells by ubiquitin. 1502 88

CARF, a collaborator of ARF (alternative reading frame protein), was cloned as a novel ARF-binding protein from a yeast-interaction screen. It potentiated ARF-mediated p53 function, and also caused a moderate increase in p53 activity in the absence of ARF. We herein report the molecular mechanism of ARF-independent function of CARF. By employing a variety of approaches, including overexpression of CARF, its suppression by small interfering RNA and use of protease inhibitors, we demonstrate that: (i) CARF directly interacts with wild-type p53, causing its stabilization and functional activation; and (ii) CARF and p53 levels show an inverse relationship that is instigated by a negative-feedback control via a proteasome-mediated degradation pathway.
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PMID:Alternative reading frame protein (ARF)-independent function of CARF (collaborator of ARF) involves its interactions with p53: evidence for a novel p53-activation pathway and its negative feedback control. 1510 3


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