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

Malignant cells of the mouse transformed by a variety of different agents have been found to express high levels of a 53,000 Mr phosphoprotein (designated p53). Little or no p53 can be detected in normal mouse cells. The nucleus appears to be the predominant site of p53 localization in transformed cells. p53-related antigens are also found in transformed cells of rat, hamster, rabbit, and human. In cells transformed by simian virus 40 (SV40), p53 forms a complex with SV40 tumor (t) antigen, resulting in the coprecipitation of T antigen by monoclonal p53 antibodies. Immune complexes of p53 precipitated from extracts of SV40- or methylcholanthrene-transformed cells by monoclonal p53 antibodies have protein kinase activity. This enzymatic activity is dependent upon divalent cations, utilizing Mn2+ more effectively than Mg2+. The phosphorylation of p53 in this kinase reaction has been found to involve serine and threonine, but not tyrosine residues. In view of the finding that the transforming proteins of several different oncogenic viruses have kinase activity, the association of this activity with p53 is important with regard to the possibility of a common pathway of transformation by diverse agents.
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PMID:p53 transformation-related protein: detection of an associated phosphotransferase activity. 626 26

Highly purified p53 protein from different sources was able to degrade DNA with a 3'-to-5' polarity, yielding deoxynucleoside monophosphates as reaction products. This exonuclease activity was dependent on Mg2+ and inhibited by addition of 5 mM nucleoside monophosphates. This exonuclease activity is intrinsic to the wild-type p53 protein: it copurified with p53 during p53 preparation; only purified wild-type p53, but not identically purified mutant p53 proteins displayed exonuclease activity; the exonuclease activity could be reconstituted from SDS gel-purified and urea-renatured p53 protein and mapped to the core domain of the p53 molecule; and finally, purified p53 protein could be UV-cross-linked to GMP. A p53-intrinsic exonuclease activity should substantially extend our view on the role of p53 as a "guardian of the genome."
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PMID:p53 Protein exhibits 3'-to-5' exonuclease activity. 867 15

Tumor necrosis factor (TNF) stimulates generation of reactive oxygen intermediates, secretion of granule constituents, and rearrangement of the cytoskeleton in neutrophils (PMN); this response requires that PMN be adherent to plasma or extracellular matrix proteins, and is dependent on beta 2 integrins. Tyrosine phosphorylation of distinct proteins [Fuortes et al., J Cell Biol 120:777-784, 1993] and activation of the protein tyrosine kinase p58c-fgr [Berton et al., J Cell Biol 126:1111-1121, 1994] were recently recognized as signals involved in beta 2 integrin-dependent responses of TNF-treated PMN. As the integrin capability to bind their ligands is regulated by divalent cations we investigated whether modulation of PMN adhesion to fibrinogen by divalent cations also affected activation of protein tyrosine kinases. In the absence of divalent cations or in the presence of Ca2+ alone, PMN did not adhere to fibrinogen in response to TNF. However, Mg2+, either alone or together with Ca2+, promoted stimulated adhesion to fibrinogen. We also found that Mn2+ promoted PMN adhesion to fibrinogen without additional stimuli. Analysis of the activity of two src family tyrosine kinases, p58c-fgr and p53/56lyn, showed that their autophosphorylating kinase activity strictly correlated with adhesion. In fact, only in the presence of Mg2+, but not in the absence of divalent cations or in the presence of Ca2+ alone, TNF increased p58c-fgr and p53/56lyn kinase activities; and this was prevented by anti-CD18 antibodies. In addition, Mn2+ strongly promoted activation of p58c-fgr and p53/56lyn without additional stimuli. Analysis of tyrosine phosphorylated proteins with anti-phosphotyrosine immunoblots showed that divalent cations regulated adhesion and protein tyrosine phosphorylation in the same fashion. Detergent extraction of proteins showed that the Mg(2+)-dependent, TNF-stimulated adhesion redistributed p58c-fgr and p53/56lyn to a Triton-insoluble fraction. In addition, analysis of p58c-fgr activity allowed us to demonstrate that the fraction of p58c-fgr which became Triton-insoluble displayed a higher kinase activity. These findings establish that PMN adhesion signals for activation of two different src family tyrosine kinases. The evidence that Mn2+, a strong promoter of integrin function, induces adhesion and activation of tyrosine kinases without additional stimuli suggest the existence of a direct link between beta 2 integrins binding to fibrinogen and activation of tyrosine kinases in neutrophils.
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PMID:Activation of p58c-fgr and p53/56lyn in adherent human neutrophils: evidence for a role of divalent cations in regulating neutrophil adhesion and protein tyrosine kinase activities. 886 73

The testis is a tissue of high proliferative activity. In this organ, sperm cells (spermatozoa) are produced from stem cells (spermatogonia) by two consecutive steps of cell multiplication and spermatid cytodifferentiation. Mitotic proliferation of spermatogonia generates primary spermatocytes which enter meiosis, leading to the generation of spermatids. The number of cells entering meiosis is held constant, since outnumbering spermatogonia or premeiotic spermatocytes are eliminated by apoptosis (programmed cell death). During apoptosis, the nuclear chromatin is internucleosomally degraded by the activity of a Ca2+, Mg2+-dependent endonuclease. Recent data indicate that deoxyribonuclease I (DNase I) is identical to the apoptotic endonuclease responsible for the internucleosomal DNA degradation. Previous results using primers specific for rat parotid DNase I in a polymerase chain reaction have demonstrated the presence of DNase I-specific gene transcripts in rat testis. We have therefore analysed the presence of DNase I in rat testis by immunohistochemistry and biochemical procedures. The presence of DNase I-like endonucleolytic activity was verified enzymatically. DNase I immunoreactivity was detected in the nuclei of a few spermatogonia and premeiotic spermatocytes, but within the acrosomic vesicle of all spermatids and spermatozoa. In situ hybridisation revealed the accumulation of DNase I-specific gene transcripts in a small number of spermatogonia and/or premeiotic spermatocytes, but in a large number of spermatids. The occurrence of apoptotic DNA fragmentation was investigated by in situ end-labelling (ISEL) of free 3'-OH DNA ends and gave positive nuclear staining of only very few spermatogonia. No positive ISEL staining was observed in maturing spermatids and/or spermatozoa. These data support the notion that, within the seminiferous epithelium, the number of primary spermatocytes entering meiosis is controlled by apoptosis. In addition, they demonstrated that mature sperm cells are equipped with an endonuclease that might be used for DNA degradation during their elimination at later stages of their life span. The expression and distribution of the tumour suppressor gene product, p53, was analysed by immunostaining. Strong p53 immunoreactivity was observed in the nuclei of a number of spermatogonia, of some premeiotic spermatocytes and probably in all spermatids. Thus, p53 expression appeared to parallel that of DNase I. In contrast, p53 immunoreactivity was absent in mature spermatozoa present in the lumen of the testicular tubules or the ductus epididymidis. It is therefore proposed that at later stages of spermatid maturation most probably before their release as mature spermatozoa-the p53 gene product was either degraded or retained in residual bodies, since p53 immunoreactivity was found to be concentrated within these organelles.
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PMID:Distribution of deoxyribonuclease I (DNase I) and p53 in rat testis and their correlation with apoptosis. 891 66

Exposure of mammalian cells to ionizing radiation (IR) induces a complex array of cellular responses including cell cycle arrest and/or apoptosis. IR-induced G1 arrest has been shown to depend on the presence of the tumor suppressor p53, which acts as a transcriptional activator of several genes. p53 also plays a role in the induction of apoptosis in response to DNA damage, and this pathway can be activated by both transcription-dependent and -independent mechanisms. Here we report the identification of a novel transcript whose expression is induced in response to IR in a p53-dependent manner, and that shows homology to the type 2C protein phosphatases. We have named this novel gene, wip1. In vitro, recombinant Wip1 displayed characteristics of a type 2C phosphatase, including Mg2+ dependence and relative insensitivity to okadaic acid. Studies performed in several cell lines revealed that wip1 accumulation following IR correlates with the presence of wild-type p53. The accumulation of wip1 mRNA following IR was rapid and transient, and the protein was localized to the nucleus. Similar to waf1, ectopic expression of wip1 in human cells suppressed colony formation. These results suggest that Wip1 might contribute to growth inhibitory pathways activated in response to DNA damage in a p53-dependent manner.
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PMID:Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. 917 66

In this study we further characterized the 3'-5' exonuclease activity intrinsic to wild-type p53. We showed that this activity, like sequence-specific DNA binding, is mediated by the p53 core domain. Truncation of the C-terminal 30 amino acids of the p53 molecule enhanced the p53 exonuclease activity by at least 10-fold, indicating that this activity, like sequence-specific DNA binding, is negatively regulated by the C-terminal basic regulatory domain of p53. However, treatments which activated sequence-specific DNA binding of p53, like binding of the monoclonal antibody PAb421, which recognizes a C-terminal epitope on p53, or a higher phosphorylation status, strongly inhibited the p53 exonuclease activity. This suggests that at least on full-length p53, sequence-specific DNA binding and exonuclease activities are subject to different and seemingly opposing regulatory mechanisms. Following up the recent discovery in our laboratory that p53 recognizes and binds with high affinity to three-stranded DNA substrates mimicking early recombination intermediates (C. Dudenhoeffer, G. Rohaly, K. Will, W. Deppert, and L. Wiesmueller, Mol. Cell. Biol. 18:5332-5342), we asked whether such substrates might be degraded by the p53 exonuclease. Addition of Mg2+ ions to the binding assay indeed started the p53 exonuclease and promoted rapid degradation of the bound, but not of the unbound, substrate, indicating that specifically recognized targets can be subjected to exonucleolytic degradation by p53 under defined conditions.
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PMID:Different regulation of the p53 core domain activities 3'-to-5' exonuclease and sequence-specific DNA binding. 1002 2

The accumulation of molecular genetic defects selected during the adaptation process in the development of cisplatin-resistance was studied using progressive cisplatin-resistant variants (L1210/DDP2, L1210/DDP5, L1210/DDP10) derived from a murine leukemia cell line (L1210/0). Of these cell lines, only the most resistant L1210/DDP10 was cross-resistant to etoposide and deficient in apoptosis induced by these two drugs, indicating that resistance to DNA-damaging agents correlates with a defect in apoptosis. This defect was tightly associated with the loss of a Ca2+/Mg2+-dependent nuclear endonuclease activity present in the less cisplatin-resistant cells. Evidence is presented that p53-dependent function (a) is lost not only in the apoptosis defective L1210/DDP10 cells, but also in the apoptosis susceptible L1210/DDP5 cells; (b) is unrelated to drug-induced cell cycle perturbations. These results suggest that deficiency in the p53 pathway and resistance to DNA-damaging agents due to a defect in apoptosis are independent events.
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PMID:Alteration in p53 pathway and defect in apoptosis contribute independently to cisplatin-resistance. 1020 Apr 88

E6 is an oncoprotein implicated in cervical cancers, produced by "high-risk" human papillomaviruses. E6 is thought to promote tumorigenesis by stimulating cellular degradation of the tumour suppressor p53, but it might display other activities. Sequence similarity was recently detected between E6 and endonuclease VII, a protein of phage T4 that recognizes and cleaves four-way DNA junctions. Here, we purified recombinant E6 proteins and demonstrated that high-risk E6 s bind selectively to four-way junctions in a structure-dependent manner. Several residues in the C-terminal zinc-binding domain, the region of E6 similar to endonuclease VII, are necessary for the junction-binding activity. E6 binds to the junction as a monomer. Comparative electrophoresis shows that E6-bound junctions migrate in an extended square conformation. Magnesium inhibits the electrophoretic migration of the complexes but does not seem to influence their formation at equilibrium. This work is the first demonstration of specific binding of purified active E6 to a well-characterized DNA ligand, and suggests new modes of action of E6 in oncogenesis.
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PMID:HPV oncoprotein E6 is a structure-dependent DNA-binding protein that recognizes four-way junctions. 1069 26

In this study we show that the naturally occurring C-terminally alternative spliced p53 (referred to as AS-p53) is active as a sequence-specific DNA binding protein as well as a 3'-5'-exonuclease in the presence of Mg2+ ions. The two activities are positively correlated as the sequence-specific DNA target is more efficiently degraded than a non-specific target. In contrast, a mutated AS-p53 protein that is deficient in DNA binding lacks exonuclease activity. The use of modified p53 binding sites, where the 3'-phosphate is replaced by a phosphorothioate group, enabled the inhibition of DNA degradation under the binding conditions. We demonstrate that AS-p53 interacts with its specific DNA target by two distinct binding modes: a high-affinity mode characterized by a low-mobility protein-DNA complex at the nanomolar range, and a low-affinity mode shown by a high-mobility complex at the micromolar range. Comparison of the data on the natural and the modified p53 binding sites suggests that the high-affinity mode is related to AS-p53 function as a transcription factor and that the low-affinity mode is associated with its exonuclease activity. The implications of these findings to a specific cellular role of AS-p53 are discussed.
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PMID:DNA binding and 3'-5' exonuclease activity in the murine alternatively-spliced p53 protein. 1214 Jul 62

Mummenbrauer et al. (1996) found that P53 protein exhibits 3'-5' exonuclease activity. This exonuclease activity is intrinsic to wildtype P53 protein, dependent on Mg2+, and it can be inhibited by addition of 5 mmol/L nucleoside monophosphates. In the present study, we intended to know whether mutated P53 protein--P53 delta 37 has this 3'-5' exonuclease activity or not. The results reveal that P53 delta 37 also has 3'-5' exonuclease activity. It has more protein and more exonuclease activity, but this activity can not be inhibited by guanine monophosphate. There are many processes related to exonuclease activity in mammalian cells; for example, DNA replication, DNA recombination and DNA repair. The exonuclease activity of P53 delta 37 protein may be important in these processes.
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PMID:[P53 delta 37 protein exhibits 3'-5' exonuclease activity]. 1250 3


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