Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Endothelial cell death may contribute to tissue injury from ischemia. Little is known, however, about the characteristics of endothelial cell death in response to hypoxia. Using an in vitro model, we found that human umbilical vein endothelial cells were resistant to hypoxia-induced cell death with only a 2% reduction in viability at 24 h and 45% reduction in viability at 48 h. Overexpression of a mutant, IkappaBalpha, via adenoviral vector did not potentiate cell death in hypoxia, indicating that nuclear factor-kappaB activation was not involved in cytoprotection. Cell death in hypoxia was determined to be apoptotic by 3' labeling of DNA using terminal deoxynucleotidyl transferase staining and reversibility of cell death with a caspase inhibitor. Exposure of endothelial cells to hypoxia did not alter levels of proapoptotic and antiapoptotic Bcl-2 family members Bax and Bcl-XL by immunoblot analysis. In contrast, changes in p53 protein levels correlated with the induction of apoptosis in hypoxic endothelial cells. Inhibition of the proteasome increased p53 protein levels and accelerated cell death in hypoxia. Overexpression of p53 by adenoviral transduction was sufficient to initiate apoptosis of normoxic endothelial cells. These data provide a framework for the study of factors regulating endothelial cell survival and death in hypoxia.
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PMID:Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. 1007 3

The Hdm2 oncoprotein inhibits p53 functions by two means: (i) it blocks p53's transactivation activity and (ii) it targets p53 for degradation in a proteasome-dependent manner. Recent data indicate that Hdm2 shuttles between the nucleus and the cytoplasm and that the regulation of p53 levels by Hdm2 requires its nuclear export activity. Two different models are consistent with these observations. In the first, Hdm2 binds to p53 in the nucleus and shuttles p53 from the nucleus to the cytoplasm, and then it targets p53 to the cytoplasmic proteasome. Alternatively, Hdm2 and p53 could be exported separately from the nucleus and then associate in the cytoplasm, where Hdm2 promotes the degradation of p53. To distinguish between these two models, several Hdm2 mutants were employed. Hdm2NLS lacks the ability to enter the nucleus, whereas Hdm2NES is deficient in nuclear export. Hdm2NLS, Hdm2NES, or the combination of both mutants were unable to promote p53 degradation in the cotransfected 2KO cells (which were null for both the p53 and mdm2 genes), although wild-type Hdm2 efficiently reduced p53 levels under the same conditions. This observation is not a result of the differences in expression levels or stability between Hdm2 and these mutants. Moreover, coexpression of these mutants had no effect on wild-type Hdm-2-induced p53 destabilization. Thus, Hdm2 must shuttle p53 from the nucleus to the cytoplasm to target it for degradation in the cytoplasm.
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PMID:Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. 1007 39

Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.
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PMID:Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA double-strand breaks. 1008 48

Nerve growth factor (NGF)-induced neurite outgrowth from rat PC12 cells was coincident with elevated (>/=2-fold) levels of endogenous ubiquitin (Ub) protein conjugates, elevated rates of formation of 125I-labeled Ub approximately E1 (Ub-activating enzyme) thiol esters and 125I-labeled Ub approximately E2 (Ub carrier protein) thiol esters in vitro, and enhanced capacity to synthesize 125I-labeled Ub-protein conjugates de novo. Activities of at least four E2s were increased in NGF-treated cells, including E2(14K), a component of the N-end rule pathway. Ubiquitylation of 125 I-labeled beta-lactoglobulin was up to 4-fold greater in supernatants from NGF-treated cells versus untreated cells and was selectively inhibited by the dipeptide Leu-Ala, an inhibitor of Ub isopeptide ligase (E3). However, Ub-dependent proteolysis of 125I-labeled beta-lactoglobulin was not increased in supernatants from NGF-treated cells, suggesting that neurite outgrowth is promoted by enhanced rates of synthesis (rather than degradation) of Ub-protein conjugates. Consistent with this observation, neurite outgrowth was induced by proteasome inhibitors (lactacystin and clasto-lactacystin beta-lactone) and was associated with elevated levels of ubiquitylated protein and stabilization of the Ub-dependent substrate, p53. Lactacystin-induced neurite outgrowth was blocked by the dipeptide Leu-Ala (2 mM) but not by His-Ala. These data 1) demonstrate that the enhanced pool of ubiquitylated protein observed during neuritogenesis in PC12 cells reflects coordinated up-regulation of Ub-conjugating activity, 2) suggest that Ub-dependent proteolysis is a negative regulator of neurite outgrowth in vitro, and 3) support a role for E2(14K)/E3-mediated protein ubiquitylation in PC12 cell neurite outgrowth.
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PMID:Neurite outgrowth in PC12 cells. Distinguishing the roles of ubiquitylation and ubiquitin-dependent proteolysis. 1020 96

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.
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PMID:MDM2 interacts with MDMX through their RING finger domains. 1021 70

The E6 proteins derived from tumour associated papillomavirus types target the cellular tumour suppressor protein p53 for ubiquitin mediated degradation. In cell lines derived from cervical tumours the p53 protein is present in very low amounts, but it can be activated by appropriate DNA damaging agents, indicating that functional p53 is present within these lines. Recent studies have also shown that different polymorphic forms of the p53 protein are differentially susceptible to E6 mediated degradation. Therefore we have been interested in analysing the effects of different HPV E6 proteins upon p53 levels in a variety of cervical tumour derived cell lines. We show that inhibition of E6 mediated degradation of p53 frequently results in increased levels of p53 expression. However, there are notable exceptions to this where increased p53 levels are only obtained following DNA damage and proteasome inhibition. We also show in E6 expressing cells, that as well as p53 being targeted for degradation, the localization of p53 to the nucleus is also inhibited, consistent with previous observations which indicate that degradation of p53 is not essential for E6 mediated inhibition of p53 function. These results have important implications for any potential therapies which might aim to block E6 mediated degradation of p53.
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PMID:Inhibition of E6 induced degradation of p53 is not sufficient for stabilization of p53 protein in cervical tumour derived cell lines. 1036 51

The c-Fos and c-Jun oncoproteins and the p53 tumor suppressor protein are short-lived transcription factors. Several catabolic pathways contribute to their degradation in vivo. c-Fos and c-Jun are thus mostly degraded by the proteasome, but there is indirect evidence that, under certain experimental/physiological conditions, calpains participate in their destruction, at least to a limited extent. Lysosomes have also been reported to participate in the destruction of c-Fos. Along the same lines, p53 is mostly degraded following the ubiquitin/proteasome pathway and calpains also seem to participate in its degradation. Moreover, c-Fos, c-Jun and p53 turnovers are regulated upon activation of intracellular signalling cascades. All taken together, these observations underline the complexity of the mechanisms responsible for the selective destruction of proteins within cells.
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PMID:Are there multiple proteolytic pathways contributing to c-Fos, c-Jun and p53 protein degradation in vivo? 1036 46

The ubiquitin/proteasome pathway mediates the degradation of many short-lived proteins that are critically involved in the regulation of cell proliferation and cell death, including the tumor suppressor protein p53. Accumulation of p53 and induction of apoptosis in RAW 264.7 macrophages in response to nitric oxide are well established. However, the molecular mechanisms involved in nitric oxide-induced p53 accumulation are unknown. Here we show that, similar to nitric oxide, treatment of macrophages with specific proteasome inhibitors, including clastolactacystin-beta-lactone, induces p53 accumulation and apoptosis, suggesting that nitric oxide may affect the activity of the proteasome. In support of this hypothesis, both exposure of cells to S-nitrosoglutathione and stimulation of endogenous nitric oxide production by lipopolysaccharide/interferon-gamma treatment result in inhibition of proteasome activity as measured in vitro by the degradation of the proteasome-specific substrate succinyl-Leu-Leu-Val-Tyr-4-methylcoumarin-7-amide. Moreover, chemically diverse nitric oxide donors interfere with proteasome-mediated degradation of polyubiquitinated p53 in vitro. These data imply that nitric oxide-induced apoptosis and accumulation of p53 are, at least in part, mediated by inhibition of the proteasome.
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PMID:Activation of the cell death program by nitric oxide involves inhibition of the proteasome. 1039 92


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