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

The p53 gene product has been implicated in both human and animal tumorigenesis. p53 forms heterologous complexes with the transforming proteins encoded by several different DNA tumor viruses. p53 also assembles into stable homo-oligomers. We demonstrate that the major structural determinant for the tetramerization of p53 is an alpha-helical plus basic region motif near the C-terminus of the protein. A monomeric p53 mutant adopts a conformation distinct from both 'wild-type' and 'mutant' form as defined by PAb1620 and PAb240 monoclonal antibody recognition. Nevertheless, monomeric and dimeric mutant p53 proteins retain the ability to suppress SV40 origin-directed DNA replication in vivo. Thus, p53-p53 interaction and expression of the PAb1620 epitope is not a prerequisite for such activity. We present data suggesting that suppression of replication by p53 may occur by a mechanism that is independent of detectable p53-T antigen association.
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PMID:A C-terminal alpha-helix plus basic region motif is the major structural determinant of p53 tetramerization. 132 1

A covalent dimer of interleukin (IL)-2, produced in vitro by the action of a nerve-derived transglutaminase, has been shown previously to be cytotoxic to mature rat brain oligodendrocytes. Here we report that this cytotoxic effect operates via programmed cell death (apoptosis) and that the p53 tumor suppressor gene is involved directly in the process. The apoptotic death of mature rat brain oligodendrocytes in culture following treatment with dimeric IL-2 was demonstrated by chromatin condensation and internucleosomal DNA fragmentation. The peak of apoptosis was observed 16-24 h after treatment, while the commitment to death was already observed after 3-4 h. An involvement of p53 in this process was indicated by the shift in location of constitutively expressed endogenous p53 from the cytoplasm to the nucleus, as early as 15 min after exposure to dimeric IL-2. Moreover, infection with a recombinant retrovirus encoding a C-terminal p53 miniprotein, shown previously to act as a dominant negative inhibitor of endogenous wild-type p53 activity, protected these cells from apoptosis.
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PMID:Direct involvement of p53 in programmed cell death of oligodendrocytes. 772 Jul 4

The structural stability of an amino acid fragment containing the oligomerization domain (residues 303-366) of the tumor suppressor p53 has been studied using high-precision differential scanning calorimetry (DSC) and circular dichroism spectroscopy (CD). Previous NMR solution structural determinations have revealed that the fragment forms a symmetric 29.8 kDa tetramer composed of a dimer of dimers (p53tet) [Lee, W., Harvey, T. S., Yin, Y., Yau, P., Litchfield, D., & Arrowsmith, C. H. (1994) Nature Struct. Biol. 1, 877-890]. Thermal unfolding of the tetramer is reversible and can be described as a two-state transition in which the folded tetramer is converted directly to unfolded monomers (N4<==>4U). According to the DSC and CD data, the population of intermediate species consisting of folded monomers or dimers is insignificant, indicating that isolated dimeric or monomeric structures have a much lower stability than the dimer and do not become populated during thermal denaturation under the conditions studied. The transition temperature of unfolding is found to be highly dependent on protein concentration and to follow the expected behavior for a tetramer that dissociates upon unfolding. Experiments conducted at pH 4.0 in 25 mM sodium acetate at a tetramer concentration of 145.8 microM have a transition temperature (Tm) of 75.3 degrees C while at 0.5 microM the value drops to 39.2 degrees C. The enthalpy change of unfolding at 60 degrees C is 26 kcal (mol of monomer)-1 with a heat capacity change of 387 cal (K.mol of monomer)-1. The stability of p53tet is dependent on pH and salt concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thermodynamic analysis of the structural stability of the tetrameric oligomerization domain of p53 tumor suppressor. 772 92

A key activity of the p53 protein during suppression of cell growth is its ability to stimulate transcription from promoters of cellular genes which contain a p53 responsive element. The E6 proteins from the oncogenic associated Human Papillomaviruses (HPVs) have been shown to inhibit specifically the p53 transcriptional activation and this has been proposed as a mechanism whereby the virus prevents the suppression of cell cycle progression and the induction of apoptosis. However, the mechanism by which E6 exercises this function is unknown, as is the ability of E6 to associate with different oligomeric forms of p53. In this study we demonstrate that E6 induces changes within the p53 protein which result both in inhibition of DNA binding and in dissociation of p53 protein previously bound to the DNA. These activities correlate exactly with the ability of E6 to inhibit p53 transcriptional activation and are independent of the ability of E6 to direct the degradation of the p53 protein. Further, we show that E6 labels wild type tetrameric and dimeric forms of p53 proteins for ubiquitin mediated degradation more readily than monomeric forms of the protein. However, in vivo analyses indicate that E6 is capable of inhibiting the transcriptional activation induced by the tetrameric, dimeric and monomeric forms of p53.
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PMID:HPV-18 E6 mediated inhibition of p53 DNA binding activity is independent of E6 induced degradation. 783 26

ERGIC-53 (former designation, p53) is a 53-kDa nonglycosylated, dimeric, and hexameric type I membrane protein that has been established as a marker protein for a tubulovesicular intermediate compartment in which protein transport from the endoplasmic reticulum to the Golgi apparatus is blocked at 15 degrees C. Although ERGIC-53 is not a resident protein of the rough endoplasmic reticulum its cDNA sequence carries a double lysine endoplasmic reticulum retention motif at the cytoplasmically exposed COOH terminus. Here we report that overexpression of ERGIC-53 in COS cells saturates its intracellular retention system leading to the appearance of ERGIC-53 at the cell surface. Cell surface ERGIC-53 is efficiently endocytosed by a mechanism that is disturbed when the two critical lysines of the endoplasmic reticulum retention motif are replaced by serines. The results suggest a mechanistic similarity of pre-Golgi retention by the double lysine motif and lysine-based endocytosis.
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PMID:A dual role for COOH-terminal lysine residues in pre-Golgi retention and endocytosis of ERGIC-53. 811 75

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

It is generally accepted that wild type (growth suppressing) p53 is capable of binding to a consensus DNA sequence and is in a conformation recognizable by antibody PAb246 (for murine p53), but not by antibody PAb240. Conversely, mutant forms of p53 incapable of DNA binding often assume conformations that display the PAb240, but not the PAb246 epitope. Exposure of these two epitopes on p53 is therefore believed to be mutually exclusive. We show that wild type p53 translated in vitro in rabbit reticulocyte lysate (RRL) has a PAb240 epitope that is not always cryptic, even on p53 that is bound sequence-specifically to DNA (presumably as a tetramer). All of the DNA-bound, PAb240+ p53 concurrently displays the PAb246 epitope, and both epitopes can be occupied by antibody while p53 is bound to DNA. This novel 'dual positive' conformation also exists in the absence of DNA and suggests that p53 is not necessarily inactive when the PAb240 epitope is displayed. When the C-terminal 58 amino acids of p53 containing the dimer/tetramerization domains are replaced with a heterologous dimerization domain, the resultant dimeric p53 manifests only the PAb246+/PAb240- conformation while bound to DNA. Thus, the C-terminal 58 amino acids of p53 are required for the PAb246+/PAb240+ phenotype, possibly due to tetramerization. This novel 'dual positive' p53 conformation exists in an excess of wild type p53 that has the PAb246-/PAb240+ 'mutant' conformation, suggesting that the 'mutant' conformation is not dominant negative in and of itself.
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PMID:A PAb240+ conformation of wild type p53 binds DNA. 880 4

We report in this work a human-derived self-assembling polypeptide based on the tetramerization domain of the human transcription factor p53, which can be fused to single-chain Fv Ab (scFv) fragments via a long and flexible hinge sequence of human origin, allowing exploitation of the functional affinity increase of binding to a ligand or cell surface with multimeric binding sites. We have demonstrated the use of this polypeptide by applying it to the construction of a tetrameric scFv against the tumor-associated carbohydrate Ag Lewis Y (Fuc alpha 1-->2Gal beta 1-->4[Fuc alpha 1-->3] GlcNAc beta 1-->3R). For comparison purposes, the corresponding scFv and dimeric mini-antibody, comprising the scFv fused via a flexible murine hinge to an artificial dimerization domain, were also created. The recombinant mini-antibody proteins were expressed in functional form in Escherichia coli and showed the expected m.w. of a dimer and tetramer, respectively. Analysis of Lewis Y-binding behavior by surface plasmon resonance revealed specific but very weak binding of the scFv fragment. In contrast, both dimeric and tetrameric scFv fusion proteins exhibited an enormous gain in functional affinity that was greatest in the case of the tetrameric mini-antibody.
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PMID:Multivalent antibody fragments with high functional affinity for a tumor-associated carbohydrate antigen. 881 7

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

The carboxy-terminal portion of the p53 protein contains the tetramerization domain, and the introduction of multiple missense mutations in this domain disrupts the formation of p53 tetramers, resulting in the production of dimeric or monomeric forms of p53. It has recently been shown that a single missense or nonsense mutation in this domain affects the functional properties of p53 both in yeast and in mammalian cells. In this study, we tested the oligomerization of p53 with mutations in the oligomerization domain, when expressed in a human osteosarcoma cell line, Saos-2, in vivo. We found that single point mutations, including two missense and two nonsense mutations, in the alpha-helix of the oligomerization domain disrupted the oligomerization of p53, but that p53 still retained its ability to inhibit colony formation of cells to some degree. These results suggest that oligomerization and the carboxy-terminal basic domain are not prerequisite for p53-dependent tumor suppression, and this may explain why few of the tumor-derived p53 mutations that have been examined so far are carboxy-terminal mutations.
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PMID:Oligomerization is not essential for growth suppression by p53 in p53-deficient osteosarcoma Saos-2 cells. 912 51


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