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 tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.
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PMID:Regulation of p53 stability by Mdm2. 915 96

The human epidermoid carcinoma-derived cell line MA1, established by introduction of the adenovirus E1A 12 S cDNA linked to the hormone-inducible promoter, elicits apoptosis after induction of E1A12 S in response to dexamethasone. E1A expression caused accumulation of wild type p53 more than 10-fold within 24 h after dexamethasone treatment. The cell lines that express E1A mutants containing a deletion either in the amino terminus or the conserved region 1 were unable to accumulate p53. p53 accumulated was degraded efficiently in vitro in the S10-0 extract (S10-0) prepared from MA1 cells in an ATP and ubiquitin-dependent manner, but not in S10-24 prepared after treatment with dexamethasone for 24 h. The p53 polyubiquitination activity in S100-0 was calcium-dependent and reduced greatly in S100-24. Ubiquitin affinity chromatography revealed that p53 ubiquitination activity in eluates thought to contain ubiquitin-conjugating enzymes decreased greatly in S100-24 as compared with S100-0. The accumulation of p53 was accompanied by the increase in the level of Mdm2, which has been shown to degrade p53 through binding to it. The high p53 level, however, was maintained until the late stage of the apoptotic process. These results indicate that the stabilization of p53 by E1A occurs through modification of a ubiquitin-specific enzyme(s) in the ubiquitin-proteasome pathway.
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PMID:Stabilization of p53 by adenovirus E1A occurs through its amino-terminal region by modification of the ubiquitin-proteasome pathway. 968 42

The stability of the p53 tumor suppressor protein is regulated by interaction with Mdm2, the product of a p53-inducible gene. Mdm2-targeted degradation of p53 depends on the interaction between the two proteins and is mediated by the proteasome. We show here that in addition to the N-terminal Mdm2 binding domain, the C terminus of p53 participates in the ability of p53 to be degraded by Mdm2. In contrast, alterations in the central DNA binding domain of p53, which change the conformation of the p53 protein, do not abrogate the sensitivity of the protein to Mdm2-mediated degradation. The importance of the C-terminal oligomerization domain to Mdm2-targeted degradation of p53 is likely to reflect the importance of oligomerization of the full-length p53 protein for interaction with Mdm2, as previously shown in vitro. Interestingly, the extreme C-terminal region of p53, outside the oligomerization domain, was also shown to be necessary for efficient degradation, and deletion of this region stabilized the protein without abrogating its ability to bind to Mdm2. Mdm2-resistant p53 mutants were not further stabilized following DNA damage, supporting a role for Mdm2 as the principal regulator of p53 stability in cells. The extreme C terminus of the p53 protein has previously been shown to contain several regulatory elements, raising the possibility that either allosteric regulation of p53 by this domain or interaction between this region and a third protein plays a role in determining the sensitivity of p53 to Mdm2-directed degradation.
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PMID:Regulation of Mdm2-directed degradation by the C terminus of p53. 974 86

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21Waf1, Mdm2, and p27Kip1. Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the up-regulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-X(L), Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of delta(psi)m. Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the delta(psi)m disruption.
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PMID:Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. 998 1

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.
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PMID:Functions of the MDM2 oncoprotein. 1006 55

Degradation of the p53 tumor suppressor protein has been shown to be regulated by Mdm2. In this study, we identify regions of Mdm2 that are not required for p53 binding but are essential for degradation. Mdm2 mutants lacking these regions function in a dominant negative fashion, stabilizing endogenous p53 in cells by interfering with the degradative function of the endogenous Mdm2. p53 protein stabilized in this way does not strongly enhance the expression of p21(Waf1/Cip1), the product of a p53-responsive gene, supporting the model in which binding of Mdm2 to the NH2-terminal domain of p53 inhibits interaction with other components of the basal transcriptional machinery. Interestingly, COOH-terminal truncations of Mdm2 that retain p53 binding but fail to mediate its degradation are also stabilized themselves. Because Mdm2, like p53, is normally an unstable protein that is degraded through the proteasome, this result suggests a direct link between the regulation of Mdm2 and p53 stability.
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PMID:Analysis of the degradation function of Mdm2. 1007 2

The Mdm2 oncoprotein mediates p53 degradation at cytoplasmic proteasomes and is the principal regulator for maintaining low, often undetectable levels of p53 in unstressed cells. However, a subset of human tumors including neuroblastoma constitutively harbor high levels of wild type p53 protein localized to the cytoplasm. Here we show that the abnormal p53 accumulation in such cells is due to a profound resistance to Mdm2-mediated degradation. Overexpression of Mdm2 in neuroblastoma (NB)(1) cell lines failed to decrease the high steady state levels of endogenous p53. Moreover, exogenous p53, when introduced into these cells, was also resistant to Mdm2-directed degradation. This resistance is not due to a lack of Mdm2 expression in NB cells or a lack of p53-Mdm2 interaction, nor is it due to a deficiency in the ubiquitination state of p53 or proteasome dysfunction. Instead, Mdm2-resistant p53 from NB cells is associated with covalent modification of p53 and masking of the modification-sensitive PAb 421 epitope. This system provides evidence for an important level of regulation of Mdm2-directed p53 destruction in vivo that is linked to p53 modification.
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PMID:Cytoplasmically "sequestered" wild type p53 protein is resistant to Mdm2-mediated degradation. 1048 81

Stabilization of p53 in response to DNA damage is caused by its dissociation from Mdm2, a protein that targets p53 for degradation in the proteasome. Dissociation of p53 from Mdm2 could be caused by DNA damage-induced p53 posttranslational modifications. The ATM and ATR kinases, whose activation in response to ionizing radiation (IR) and UV light, respectively, is required for p53 stabilization, directly phosphorylate p53 on Ser-15. However, phosphorylation of Ser-15 is critical for the apoptotic activity of p53 and not for p53 stabilization. Thus, whether any p53 modifications, and which, underlie disruption of the p53-Mdm2 complex after DNA damage remains to be determined. We analyzed the IR- and UV light-induced stabilization of p53 proteins with substitutions of Ser known to be posttranslationally modified after DNA damage. Substitution of Ser-20 was sufficient to abrogate p53 stabilization in response to both IR and UV light. Furthermore, both IR and UV light induced phosphorylation of p53 on Ser-20, which involved the majority of nuclear p53 protein and weakened the interaction of p53 with Mdm2 in vitro. ATM and ATR cannot phosphorylate p53 on Ser-20. We therefore propose that ATM and ATR activate an, as yet unidentified, kinase that stabilizes p53 by phosphorylating it on Ser-20.
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PMID:Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. 1057 Jan 49

The p53 homologue p73 efficiently activates p53-responsive genes. The well documented over-expression of p73 spliced forms in a wide variety of tumor types promoted us to elucidate the mechanisms underlying p73-mediated transcription. Using the luciferase reporter gene driven by Mdm2-minimal promoter in p53 null cells, we demonstrate that the weak transcriptional activity mediated by p73alpha was increased by the mutant form p73beta292, which by itself is transcriptionally inactive. Similarly, cooperation between p73beta and an inactive form of p73alpha increased p73beta-mediated transcriptional activities. Conversely, p73beta elicited a silencing effect on a gain of function mutant, p53(281), which by itself mediated efficient transactivation of the MDR promoter. Neither anisomycin nor actinomycin D altered p73-mediated transcriptional activities, whereas sorbitol profoundly inhibited them through a rapid proteasome-dependent degradation of p73. Our observations point to plausible scenarios in which p73, through cooperation between p73 spliced forms and suppression of gain of function mutant p53 may elicit changes in the transcription of p53 target genes that play key roles in cell growth and death.
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PMID:p73 transcriptional activity increases upon cooperation between its spliced forms. 1069 2

Mdm2 is a nuclear phosphoprotein which functions as a negative feedback regulator of the p53 tumor suppressor gene. In this study, we investigated the alteration of Mdm2 and p53 in three human cancer cell lines containing either a wild-type or mutant p53 gene after treatment with Adriamycin (doxorubicin, ADR), a DNA damaging agent. We found that human breast cancer MCF-7 cells containing wild-type p53 were much more susceptible to ADR compared to human breast cancer MDA-MB-231 and human prostate cancer Du-145 cells which contain mutant p53. ADR resulted in a significant dose-dependent accumulation of p53 protein in MCF-7 cells, whereas little or no influence was observed on p53 protein of the two mutant p53 cell lines. However, a significant down-regulation of Mdm2 at protein and mRNA levels was observed in these three cell lines following ADR treatment. Moreover, the decrease of Mdm2 was in both a dose- and time-dependent manner. It is interestingly noted that 5 microM is a critical dose for significant down-regulation of the Mdm2 protein. Selected proteasome inhibitors did not rescue the ADR-caused decline in the expression of Mdm2 protein. Therefore, our present results reveal that ADR can induce a down-regulation of Mdm2 via a p53-independent pathway in human cancer cells and the ubiquitin-proteasome degradation mechanism may not be involved in the decreased expression of Mdm2 protein.
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PMID:P53-independent down-regulation of Mdm2 in human cancer cells treated with adriamycin. 1077 10


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