Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor p53 is degraded by the ubiquitin-proteasome system. p53 was polyubiquitinated in the presence of E1, UbcH5 as E2 and MDM2 oncoprotein. A ubiquitin molecule bound MDM2 through sulfhydroxy bond which is characteristic of ubiquitin ligase (E3)-ubiquitin binding. The cysteine residue in the carboxyl terminus of MDM2 was essential for the activity. These data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus-uninfected cells which do not have E6 protein.
 ...
PMID:Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. 945 May 43

The p53 protein is activated in response to physiological stress resulting in either a G1 arrest of cells or apoptosis. As such, p53 must be tightly regulated, and the MDM2 oncoprotein plays a central role in that regulatory process. The transcription of the Mdm2 oncogene is induced by the p53 protein after DNA damage, and the MDM2 protein then binds to p53 and blocks its activities as a tumour suppressor and promotes its degradation. These two proteins thus form an autoregulatory feedback loop in which p53 positively regulates MDM2 levels and MDM2 negatively regulates p53 levels and activity. Immediately after ultraviolet (UV) irradiation MDM2 messenger RNA and protein levels fall in a p53-independent fashion, resulting in increased p53 levels. The p53 protein is then activated as a transcription factor by posttranslational modification permitting p53 to initiate its cell-cycle arrest or apoptotic (programmed cell death) functions. At later times, after the repair of DNA, MDM2 levels increase in a p53-dependent fashion. This induction of MDM2 results in the inhibition of p53 transcriptional activity and the degradation of p53 protein. MDM2-p53 complexes in the nucleus are transported to the cytoplasm via signals present in the MDM2 protein, where p53 is degraded in the proteasome. Thus MDM2 acts as a nuclear-cytoplasmic shuttle for the p53 protein. There are many levels at which this process is regulated, and as such there are many places for chemotherapeutic interventions. The amino-terminal domain of the MDM2 protein is all that is required to bind the p53 protein. The MDM2 protein has additional domains and therefore may have additional functions. Any of these MDM2 domains may contribute to MDM2's activities as an oncogene independent of its inhibition of the tumour suppressor functions of p53. Thus MDM2 itself could be a target for cancer therapeutic intervention.
 ...
PMID:Functions of the MDM2 oncoprotein. 1006 55

The N-terminus of MDM2 proto-oncoprotein interacts with p53 and down modulates p53 activity by inhibiting transcriptional activity and promoting p53 degradation. MDMX is structurally related to MDM2 and also binds to p53. However, the function of MDMX has not been clarified yet. We found that MDM2 hetero-oligomerized with MDMX through their C-terminal RING finger domains. Yeast two-hybrid analysis revealed that the hetero-oligomerization between MDMX and MDM2 was more stable than the homo-oligomerization of each protein. MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2.
 ...
PMID:MDM2 interacts with MDMX through their RING finger domains. 1021 70

The p53 gene encodes one of the most important tumor suppressors in human cells and undergoes frequent mutational inactivation in cancers. MDM2, a transcriptional target of p53, binds p53 and can both inhibit p53-mediated transcription [1] [2] and target p53 for proteasome-mediated proteolysis [3] [4]. A close relative of p53, p73, has recently been identified [5] [6]. Here, we report that, like p53, p73alpha and the alternative transcription product p73beta also bind MDM2. Interaction between MDM2 and p53 represents a key step in the regulation of p53, as MDM2 promotes the degradation of p53. In striking contrast to p53, the half-life of p73 was found to be increased by binding to MDM2. Like MDM2, the MDM2-related protein MDMX also bound p73 and stabilized the level of p73. Moreover, the growth suppression functions of p73 and the induction of endogenous p21, a major mediator of the p53-dependent growth arrest pathway, were enhanced in the presence of MDM2. These differences between the regulation of p53 and p73 by MDM2/MDMX may highlight a physiological difference in their action.
 ...
PMID:MDM2 and MDMX bind and stabilize the p53-related protein p73. 1046 68

The p53 tumor suppressor is regulated by the MDM2 oncoprotein through a negative feedback mechanism. MDM2 promotes the ubiquitination and proteasome-dependent degradation of p53, possibly by acting as a ubiquitin ligase. In cervical cancer cells containing high-risk human papillomaviruses (HPV), p53 is also targeted for degradation by the HPV E6 oncoprotein in combination with the cellular E6-AP ubiquitin ligase. In this report, we describe the identification of efficient antisense oligonucleotides against human E6-AP. The roles of MDM2 and E6-AP in p53 regulation were investigated using a novel E6-AP antisense oligonucleotide and a previously characterized MDM2 antisense oligonucleotide. In HPV16-positive and HPV-18 positive cervical cancer cells, inhibition of E6-AP, but not MDM2, expression results in significant induction of p53. In HPV-negative tumor cells, p53 is activated by inhibition of MDM2 but not E6-AP. Furthermore, treatment with both E6-AP and MDM2 antisense oligonucleotides in HPV-positive cells does not lead to further induction of p53 over inhibition of E6-AP alone. Therefore, E6-AP-mediated degradation is dominant over MDM2 in cervical cancer cells but does not have a significant role in HPV-negative cells.
 ...
PMID:The roles of E6-AP and MDM2 in p53 regulation in human papillomavirus-positive cervical cancer cells. 1072 57

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.
 ...
PMID:Stress signals utilize multiple pathways to stabilize p53. 1075 6

MDM2 can bind to p53 and promote its ubiquitination and subsequent degradation by the proteasome. Current models propose that nuclear export of p53 is required for MDM2-mediated degradation, although the function of MDM2 in p53 nuclear export has not been clarified. Here we show that MDM2 can promote the nuclear export of p53 in transiently transfected cells. This activity requires the nuclear-export signal (NES) of p53, but not the NES of MDM2. A mutation within the MDM2 RING-finger domain that inhibits p53 ubiquitination also inhibits the ability of MDM2 to promote p53 nuclear export. Finally, inhibition of nuclear export stabilizes wild-type p53 and leads to accumulation of ubiquitinated p53 in the nucleus. Our results indicate that MDM2-mediated ubiquitination, or other activities associated with the RING-finger domain, can stimulate the export of p53 to the cytoplasm through the activity of the p53 NES.
 ...
PMID:The MDM2 RING-finger domain is required to promote p53 nuclear export. 1098 Jun 96

Control of proliferation and differentiation by the retinoblastoma tumor suppressor protein (pRB) and related family members depends upon their interactions with key cellular substrates. Efforts to identify such cellular targets led to the isolation of a novel protein, EID-1 (for E1A-like inhibitor of differentiation 1). Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. EID-1 is rapidly degraded by the proteasome as cells exit the cell cycle. Ubiquitination of EID-1 requires an intact C-terminal region that is also necessary for stable binding to p300 and pRB, two proteins that bind to the ubiquitin ligase MDM2. A pRB variant that can bind to EID1, but not MDM2, stabilizes EID-1 in cells. Thus, EID-1 may act at a nodal point that couples cell cycle exit to the transcriptional activation of genes required for differentiation.
 ...
PMID:Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle. 1107 89

The p53 tumor suppressor protein and the MDM2 oncoprotein form a feedback-control loop that up-regulates cellular MDM2 production, blocks p53 activity, and promotes p53 decay. tsg101 was discovered as a gene whose deficiency results in neoplastic transformation of NIH 3T3 cells and the ability to generate metastatic tumors in nude mice. Its protein product contains a domain, Ubc, characteristic of the catalytic domain of ubiquitin conjugase (E2) enzymes but lacking an active-site cysteine crucial for ubiquitin conjugase activity. Here we report that TSG101 participates with MDM2 in an autoregulatory loop that modulates the cellular levels of both proteins, and also of p53, by affecting protein decay. We show that the Ubc domain of TSG101 interferes with ubiquitination of MDM2, that TSG101 inhibits MDM2 decay and elevates its steady-state level, and that these events are associated with down-regulation of p53 protein. Conversely, pulse-chase and Western blot experiments in wild-type and mutant fibroblasts indicate that elevation of MDM2 by overexpression of wild-type p53, by amplification of the endogenous MDM2 gene, or by transfection of MDM2-expressing constructs promotes TSG101 loss, which we show occurs by 26S proteasome-dependent decay. Our results identify TSG101 as both a regulator of, and target of, MDM2/p53 circuitry.
 ...
PMID:A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. 1117

The wild type p53 tumor suppressor protein is rapidly degraded in normal cells by MDM2, the ubiquitin ligase that serves as the key regulator of p53 function by modulating protein stability. Cellular exposure to genotoxic stress triggers the stabilization of p53 by multiple pathways that converge upon interference with MDM2 function. In this study, we first investigated the ability of HDM2 (MDM2 human homologue) to degrade endogenous p53 in neuroblastoma (NB). Although the p53 protein in NB has been reported to be constitutively stabilized, we find that HDM2 in NB is functional and facilitates the rapid turnover of p53 in nonstressed cells via the proteasome pathway. Second, we examined the relationship between p53 and HDM2 in the adriamycin-mediated stabilization of p53 in NB. We demonstrate that while p53 stabilization depends neither upon the phosphorylation of specific N-terminal sites nor upon dissociation from HDM2, it requires inactivation of functional HDM2. In support of this notion, p53 stabilization following adriamycin resulted in an inhibition of both p53 ubiquitination and HDM2 ligase activity. Taken together, these data implicate a requirement for enzymatic inactivation of HDM2 as a novel mechanism for p53 stabilization in the DNA damage response pathway.
 ...
PMID:Requirement for HDM2 activity in the rapid degradation of p53 in neuroblastoma. 1127 10


1 2 3 4 5 6 7 8 9 10 Next >>