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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of the tumor suppressor protein p53 are generally quite low in normal cells, due in part to its rapid turnover. Previous studies have implicated ubiquitin-dependent proteolysis in the turnover of wild-type p53 but have not established whether or not p53 is itself a substrate of the ubiquitin system. In this study, inhibitors of the 26S proteasome have been used to further explore the role of ubiquitin proteolysis in regulating p53 turnover. Increased levels of the tumor suppressor protein p53 were observed in normal cells, as well as in cells expressing the human papillomavirus 16 E6 oncoprotein, on exposure of the cells to proteasome inhibitors. Pulse-chase experiments indicated that the increased p53 levels resulted from stabilization of the protein. Furthermore, ubiquitin-p53 conjugates were detected in untreated as well as gamma-irradiated cells, indicating that ubiquitin-dependent proteolysis plays a role in the normal turnover of p53. Increased levels of the cyclin:cyclin-dependent kinase inhibitor p21, a downstream effector of p53 function, were also observed in proteasome inhibitor-treated cells, and this increase was due in part to an increase in p2l mRNA.
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PMID:In vivo ubiquitination and proteasome-mediated degradation of p53(1). 865 11

Ubiquitin-conjugating enzymes (E2s) are essential components of the post-translational protein ubiquitination pathway, mediating the transfer of activated ubiquitin to substrate proteins. We have identified a human gene, UBE2L3, localized on Chromosome (Chr) 22q11. 2-13.1, encoding an E2 almost identical to that encoded by the recently described human L-UBC (UBE2L1) gene present on Chr 14q24.3. Using chromosome-specific vectorette PCR, we have determined the intron/exon structure of UBE2L3. In contrast to the intronless UBE2L1 gene, the coding sequence of UBE2L3 is interrupted by three large introns. UBE2L3-derived mRNA appears to be the predominant species in most tissues rather than the transcript from UBE2L1 or another homologous gene UBE2L2, which maps to Chr 12q12. We also present additional evidence that these genes are members of a larger multigene family. The primary sequence of the protein encoded by UBE2L3 is identical to partial peptide sequence derived from the rabbit E2 'E2-F1,' suggesting that we have identified the human homolog of this protein. This latter E2 has been demonstrated to participate in transcription factor NF-kappaB maturation, c-fos degradation, and human papilloma virus-mediated p53 degradation in vitro.
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PMID:Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3. 867 31

Inhibition of p53 function is a common feature of many DNA tumour viruses. Human papillomavirus (HPV) E6 proteins from the oncogenic HPVs inhibit p53 function either by blocking its ability to bind DNA or by labelling newly synthesised p53 as a target for ubiquitin mediated degradation. In this study we have investigated the role of the degradation function of E6 with respect to p53 function. Using a panel of previously characterised p53 mutant proteins we have been able to establish a series of assays which separates p53 growth suppression from transformation suppression and from induction of apoptosis. Only wild type p53 inhibits the growth of p53 null 10(1) cells, whereas wild type, dimeric and monomeric mutants of p53 suppress transformed cell growth of both Saos-2 cells and baby rat kidney cells. Cells expressing the different oligomeric forms of p53 all retain the ability to induce apoptosis upon u.v. treatment. Using HPV E6 and E7 we have been able to show that E7 will overcome p53 growth suppressor activity with an efficiency similar to that observed with E6. However, in contrast to E6, E7 has no effect on the ability of p53 to suppress transformed cell growth. Finally, we show that the ability of E6 to label p53 for ubiquitin mediated degradation is prerequisite for its ability to overcome p53 inhibition of transformed cell growth and induction of apoptosis. These observations argue that E6 inhibits p53 mediated apoptosis and suppression of transformation while E7 inhibits p53 suppression of cell proliferation.
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PMID:Induction of apoptosis by p53 is independent of its oligomeric state and can be abolished by HPV-18 E6 through ubiquitin mediated degradation. 871 Mar 65

The proteasome and the small protein ubiquitin are key elements in the intracellular pathway of general protein degradation. Recent evidence shows that the proteasome and other less well defined cytoplasmic proteases can participate in specific events which control inducible gene expression. A number of eukaryotic transcriptional regulators, including NF-kappa B/l kappa B, p53, c-Jun, Notch, sterol regulated element binding proteins and MAT2 alpha, have recently been shown to be regulated by proteolytic events, a regulation which results in the activation or inactivation of gene expression.
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PMID:Control of gene expression by proteolysis. 874 84

The E6 proteins of the oncogenic-associated human papillomavirus types 16 (HPV-16) and 18 (HPV-18) function by interfering with the normal cell cycle control mechanisms, particularly those controlled by p53. HPV E6 is able to interfere with p53 function by preventing its binding to DNA target sequences and also by labelling p53 for ubiquitin-mediated degradation. We have previously reported that certain p53 mutants, defective in oligomerisation, vary in their susceptibility to E6-directed labelling for ubiquitin-mediated degradation. In this paper we report that the strength of p53's binding to DNA is dependent upon the precise target sequence, but that E6 is able to disrupt each complex. We also report the binding of different oligomeric forms of p53 to different DNA sequences and correlate this with in vivo transcriptional activity and demonstrate the susceptibility of that DNA binding to disruption by E6. Finally we show that the ability of p53 to bind to TBP is a function of its oligomeric state and correlates in part with its ability to transrepress but not with its ability to transactivate.
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PMID:HPV-18 E6 inhibits p53 DNA binding activity regardless of the oligomeric state of p53 or the exact p53 recognition sequence. 876 Feb 88

This retrospective immunohistochemical study compares the expression of five stress-response (heat-shock) proteins (srp's) [srp 90, srp 72, srp 27, alpha B-crystallin and ubiquitin], p53 protein and proliferating cell nuclear antigen (PCNA) in 118 primary brain tumors and 21 carcinoma metastases to the central nervous system. Serial sections of formalin-fixed, paraffin-embedded tissues were used. Most astrocytomas (9/13), ependymomas (5/5), glioblastoma multiforme (GBM) (11/12), schwannomas (19/21), meningiomas (22/23) and breast carcinoma metastases (Br-Mt) (9/10), and some medulloblastomas (5/15), primitive neuroectodermal tumors (PNETs) (5/11), pituitary adenomas (4/7) and lung carcinoma metastases (6/11), but none of 10 oligodendrogliomas had tumor cells that expressed one or more (up to five) srp's. The percentage of tumors with p53-positive cells was variable; the proportion was highest among srp-expressing GBMs (mean: 16.1%) and Br-Mts (mean: 15.3%). The mean PCNA-labeling index (LI) also varied, ranging from 1.2% in the group of pituitary adenomas to 24.5% in Br-Mts, with GBMs (20.4%) and medulloblastomas (18.4%) approaching the latter value. PCNA-LI was higher in the astrocytomas, GBMs, medulloblastomas and PNETs that expressed srp's than in those did not. A high proportion of p53-positive cells (31.3 to 59.0%) and the highest PCNA-LIs (41.0 to 49.0%) were seen in two GBMs and one Br-Mt that expressed all five srp's. We conclude that primary and metastatic tumors of the brain produce one or more stress-related proteins, and that a variable proportion of the tumor cells have immunohistochemically-detectable p53, the expression of which may depend, at least in part, on the growth potential of a given tumor.
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PMID:Brain tumor: immunohistochemical studies on the stress-response proteins, p53 protein and proliferating cell nuclear antigen. 886 93

Ubiquitin-conjugating enzymes (E2 or Ubc) constitute a family of conserved proteins that play a key role in ubiquitin-dependent degradation of proteins in eukaryotes. We describe here a transgenic mouse strain where retrovirus integration into an Ubc gene, designated UbcM4, results in a recessive-lethal mutation. UbcM4 is the mouse homologue of the previously described human UbcH7 that is involved in the in vitro ubiquitination of several proteins including the tumor suppressor protein p53. The provirus is located in the first intron of the gene. When both alleles are mutated the level of steady-state mRNA is reduced by about 70%. About a third of homozygous mutant embryos die around day 11.5 of gestation. Embryos that survive that stage are growth retarded and die perinatally. The lethal phenotype is most likely caused by impairment of placenta development as this is the only organ that consistently showed pathological defects. The placental labyrinth is drastically reduced in size and vascularization is disturbed. The UbcM4 mouse mutant represents the first example in mammals of a mutation in a gene involved in ubiquitin conjugation. Its recessive-lethal phenotype demonstrates that the ubiquitin system plays an essential role during mouse development.
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PMID:Provirus integration into a gene encoding a ubiquitin-conjugating enzyme results in a placental defect and embryonic lethality. 890 95

Cell cycle progression is mainly controlled by the hetero-dimeric protein kinase complex named SPF (S-phase promoting factor) and MPF (M-phase promoting factor), consisting of CDKs and the regulator cyclins, which are involved in G1/S and G2/M transitions, respectively. Moreover, SPF is modulated by not only various oncoproteins positively, but also tumor suppresive gene products negatively. These regulator proteins are extremely unstable in cells, oscillating during cell cycle, and cell cycle stage-dependent destruction of specific factors is required for cell cycle progression, but molecular mechanism of their destabilization remains to be clarified. The ubiquitin-proteasome system is responsible for selective- and ATP-dependent degradation of various types of short-lived proteins in the cytoplasm and the nucleus. In this article, we review briefly the proteolytic pathway mediated by ubiquitin and the proteasome, and the degradation mechanism of major cell cycle protein factors, such as Mos, p53, cyclin B, Fos/Jun and NFkappaB/IkappaB.
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PMID:[Degradation mechanism of cell cycle factors by the proteasome]. 890 49

Levels of the tumor suppressor protein p53 are normally quite low due in part to its short half-life. p53 levels increase in cells exposed to DNA-damaging agents, such as radiation, and this increase is thought to be responsible for the radiation-induced G1 cell cycle arrest or delay. The mechanisms by which radiation causes an increase in p53 are currently unknown. The purpose of this study was to compare the effects of gamma and UV radiation on the stability and ubiquitination of p53 in vivo. Ubiquitin-p53 conjugates could be detected in nonirradiated and gamma-irradiated cells but not in cells which were UV treated, despite the fact that both treatments resulted in the stabilization of the p53 protein. These results demonstrate that UV and gamma radiation have different effects on ubiquitinated p53 and suggest that the UV-induced stabilization of p53 results from a loss of p53 ubiquitination. Ubiquitinated forms of p21, an inhibitor of cyclin-dependent kinases, were detected in vivo, demonstrating that p21 is also a target for degradation by the ubiquitin-dependent proteolytic pathway. However, UV and gamma radiation had no effect on the stability or in vivo ubiquitination of p21, indicating that the radiation effects on p53 are specific.
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PMID:Ubiquitination of p53 and p21 is differentially affected by ionizing and UV radiation. 897 16

Wild type p53 protein has been shown by recent investigations to be involved in the negative regulation of cell proliferation, whereas aberrant p53 protein has lost this negative regulation of cell growth. Wild type p53 protein, which has a very short half-life, has generally been considered to be undetectable using immunohistochemical methods; however, according to a recent report, wild type p53 protein may accumulate in the nuclei because of a defective ubiquitin pathway. Aberrant p53 protein has a longer half-life, and thus is visible using immunohistochemical methods. In this study, both the proliferative potential represented by the MIB-1 staining index (SI) and the immunoreactivity of p53 protein in 51 intracranial meningiomas were studied applying immunohistochemical staining methods to archival paraffin sections. The correlation among MIB-1 SI, p53 immunoreactivity, histopathologic findings and the clinical course of the meningiomas was also analyzed retrospectively. Although it is not possible with available reagents to distinguish between aberrant p53 protein and wild type p53 protein, statistical analyses show that p53 protein was immunostained both in meningiomas with high MIB-1 SI and in recurrent meningiomas. This demonstrates the close relationship among p53 immunoreactivity, MIB-1 SI, and recurrence; therefore, the presence of p53 protein by immunohistochemical examination may suggest the proliferative activity of meningioma and is capable of serving as a predictor of future recurrence.
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PMID:Correlation between MIB-1 staining index and the immunoreactivity of p53 protein in recurrent and non-recurrent meningiomas. 898 Mar 54


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