UNIPROT:P04637 - FACTA Search

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

Expression of mutated versions of the p53 gene deranged the differentiation program of thyroid cells and resulted in deregulated growth. Specifically, p53 mutants in several residues of the DNA-binding region induced thyrotropin (TSH) -independent growth and inhibition of the expression of thyroid-specific genes. The loss of the differentiated phenotype invariably correlated with the blockage of the expression of the genes coding for the thyroid transcriptional factors PAX-8 and TTF2. Conversely, thyroid cells transfected with a p53 gene mutated at codon 392, located outside the DNA-binding region, stimulated the expression of differentiation genes in the absence of the TSH, and induced TSH-independent growth. cAMP intracellular levels were higher in thyroid cells transfected with the p53 gene mutated at the 392 site than in the untransfected thyroid cells, but lower in the cells transfected with the other mutated p53 genes. Fra-1 and c-jun were induced by p53, resulting in increased AP-1 levels. The results of this study suggest that p53 exerts effects on cAMP transduction pathway in thyroid cells, which are exquisitely sensitive to cAMP.
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PMID:p53 genes mutated in the DNA binding site or at a specific COOH-terminal site exert divergent effects on thyroid cell growth and differentiation. 966 7

After more than a year had elapsed since a single oral exposure to 2 and 4 microgram 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg, there was an apparent dose-related increased incidence of significant endocervical squamous metaplasia in a group of cynomolgus macaques (Scott et al., 1998). In the present experiments we investigated the mechanisms by which chemicals like TCDD could induce epithelial cell transdifferentiation in the primate endocervix. One focus of investigation was epidermal growth factor receptor (EGFR) and the key cytosolic signaling kinases, c-Src and protein tyrosine kinase (PTK), whose responses to TCDD are well characterized. A second focus was the distal kinase Erk2 that transduces the cytosolic signal into a nuclear signal, and which in combination with nuclear casein kinase II (CKII), can lead to activation of p53. Finally, we studied three key target proteins of activated p53 (wafl/p21, Cdc2 p34, and Cdk4), whose modulation could produce cell cycle effects. The studies were carried out using primary cell cultures prepared from endocervical epithelium recovered at necropsy from TCDD-treated (2 and 4 microgram TCDD/kg) and untreated macaques. There was a significant decrease in EGFR binding activity in cells from TCDD-treated animals as compared to controls. A marked increase in the protein amount of H-Ras and a significant increase in the activity of c-Src kinase, PTK, and Erk2 were found in cells from TCDD-treated animals. A significant decrease in the activity of CKII and in the protein amount of p53, wafl/p21, and Cdc2 p34 was found. On the other hand, a substantial increase in the protein amount of Cdk4 and DNA binding activity of AP-1 was found in cells from TCDD-treated animals. In vitro experiments using primary cultures of endocervical cells from untreated macaques revealed that these cells have AhR, and that c-Src protein is functionally attached to the AhR and is specifically activated upon ligand binding as judged by the following criteria. (1) A structure-activity relationship study with TCDD and three dioxin congeners revealed a rank order for their potency in activation of AhR-associated c-Src kinase from cervical cells which was identical to that of previously determined toxicity indices. (2) TCDD-induced, AhR-associated c-Src kinase activity was abolished when an AhR immunoprecipitate from cervical cells was preincubated with alpha-naphthoflavone (AhR blocker) or geldanamycin (Src kinase inhibitor) prior to the addition of TCDD. (3) The analysis of the AhR complex showed three proteins of molecular weights of 100 (AhR), 90, and 60 kDa. (4) The same protein with molecular weight 60 kDa was found when the immunoprecipitate with anti AhR-antibody was analyzed by SDS-PAGE, then transferred into nitrocellulose membrane followed by immunobloting the membrane with anti c-Src-antibody. Our data suggest that TCDD induced pathology in endocervical cells through changes in growth factor receptor signaling, other cytosolic signaling proteins, tumor suppressor proteins, and cell cycle proteins.
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PMID:Alterations in the growth factor signal transduction pathways and modulators of the cell cycle in endocervical cells from macaques exposed to TCDD. 970 5

Prolinedithiocarbamate (PDTC) and diethyldithiocarbamate (DDTC) are cancer chemopreventive agents and can be biotransformed to prolinethiuramdisulfide (PTDS) and tetraethylthiuramdisulfide (disulfiram; DTDS), respectively. We found that the reactive metabolites PTDS and DTDS induced apoptosis after G1/S arrest. Phosphorylation of cyclin E, inhibition of cyclin-dependent kinase 2 activity, and degradation of cyclin E were found in human hepatoma Hep G2 cells during apoptosis. Moreover, PTDS and DTDS decreased the level of bcl-2 but increased the level of p53. In contrast, PDTC, DDTC, and ammonium dithiocarbamate (ADTC) did not induce apoptosis; rather they led to the induction of p53 and p21 followed by G1/S arrest. PDTC, DDTC, and ADTC also arrested cells in G1 phase. We then examined the effects of PTDS and DTDS on the signal transduction mechanisms leading to apoptosis. Although the transcription factors NFkappaB and AP-1 cooperatively decreased their DNA-binding activities to kappaB and 12-O-tetradecanoylphorbol-13-acetate-responsive elements, respectively, and p53 increased DNA-binding activity in the early stage but decreased it in the latter stage after treatment with PTDS, when the human Hep G2 cells were undergoing apoptosis. In summary, our results indicated that (i) PTDS and DTDS induced apoptosis and G1/S arrest mediated by p53, whereas PDTC, DDTC, and ADTC induced p53-dependent p21 expression leading to G1/S arrest; (ii) PDTC, DDTC, and ADTC induced p21/KIP1/CIP1 expression in a p53-dependent pathway leading to G1/S arrest; and (iii) NFkappaB, AP-1, and bcl-2 were downregulated during PTDS- and DTDS-induced apoptosis. These results suggested that PTDS and DTDS induced p53-dependent apoptosis, whereas PDTC, DDTC, and ADTC induced G1/S arrest. Apoptosis is regulated by the modulation of intracellular effectors such as NFkappaB, AP-1, and bcl-2 and activation of p53 in early stages.
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PMID:Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFkappaB, c-fos/c-jun, and p53 proteins. 972 16

Here we compared the features of apoptosis induced by DNA-damaging agent, etoposide, and by withdrawal of the growth factors in NB 2a neuroblastoma cells. We showed that serum deprivation and etoposide induced a distinct pattern of regulation of c-Fos, c-Jun and p53 protein levels, as well as the differential changes in DNA-binding activity of AP-1 and NF-kappaB transcription factors. The late phase of apoptesis induced by serum withdrawal was associated with disintegration of nuclear DNA both into high molecular weight (HMW) and oligonucleosomal DNA fragments, whereas etoposide induced the formation of HMW-DNA fragments without internucleosomal DNA cleavage. Incubation of etoposide-treated cells without serum resulted in an additive effect on the pattern of DNA fragmentation. Differences in DNA fragmentation profiles induced by serum withdrawal and etoposide in NB 2a cells were reproducible in nonproliferating cerebellar granule cells and also in a cell free system assay after treatment of isolated normal nuclei with cytosolic extracts prepared from serum-deprived or etoposide-treated cells. Both HMW and oligonucleosomal DNA fragmentation in serum-deprived cells was inhibited by aurintricarboxylic acid and was completely abrogated by cycloheximide. In contrast, DNA fragmentation in etoposide-treated cells was insensitive to the inhibitory effect of aurintricarboxylic acid, and was not prevented by cycloheximide. Our results indicate that in NB 2a neuroblastoma cells etoposide and serum withdrawal induce a distinct mode of apoptosis which is associated with a distinct pattern of regulation of immediately early response genes in the early phase, and with recruitment of different mechanisms for DNA disintegration in the late phase of apoptosis.
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PMID:Distinct mode of apoptosis induced by genotoxic agent etoposide and serum withdrawal in neuroblastoma cells. 979 26

Oxidative stress has long been implicated in the pathogenesis of both the acute and chronic neurotoxic effects of glutamate acting through ionotrophic receptors of the N-methyl-d-aspartate (NMDA) subtype. To evaluate the contribution of oxidative stress to the NMDA receptor-mediated apoptotic death of rat striatal neurons in vivo, the effects of a novel, orally administered free radical scavenger, OPC-14117, was studied following intrastriatal infusion of the NMDA receptor agonist quinolinic acid (QA). Receptor autoradiography and in situ hybridization histochemistry showed that pretreatment with OPC-14117 (600 mg/kg) reduced the QA (120 nmol)-induced loss of striatal D1 dopamine receptors by about 20% (p<0.01) and NMDA receptors by 15% (p<0.01) as well as 67 kDa glutamic acid decarboxylase mRNA (34%; p<0.01) and proenkephalin mRNA (36%; p<0.01). OPC-14117 also decreased the apomorphine-induced ipsilateral rotational response in unilaterally QA-lesioned animals by about 70% (p<0.05). In addition, OPC-14117 pretreatment inhibited QA-induced internucleosomal DNA fragmentation. Western blot analysis and electrophoresis mobility shift assay further revealed that the free radical scavenger (300 and 600 mg/kg) blunted the QA-induced degradation of IkappaBalpha (increased IkappaBalpha levels from about 15% to 33 and 62% of control, respectively; p<0.01) as well as the ensuing activation of NF-kappaB by 25 to 34%, respectively (p<0. 01) and the augmentation in c-Myc (35 to 70%, respectively) and p53 expression by 50-80%, respectively (both p<0.01). In contrast, OPC-14117 had no significant effect on the QA-induced increase in AP-1 binding activity. These results suggest that the NMDA receptor-mediated generation of reactive oxygen species contributes to the QA-induced activation of NF-kappaB and further that orally administered OPC-14117 partially protects against excitotoxin-induced apoptosis of striatal neurons through inhibition of the NF-kappaB apoptotic cascade.
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PMID:Free radical scavenger OPC-14117 attenuates quinolinic acid-induced NF-kappaB activation and apoptosis in rat striatum. 988 20

The c-jun proto-oncogene encodes a component of the mitogen-inducible immediate-early transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation and G1-to-S-phase progression. Here we report that fibroblasts derived from c-jun-/- mouse fetuses exhibit a severe proliferation defect and undergo a prolonged crisis before spontaneous immortalization. The cyclin D1- and cyclin E-dependent kinases (CDKs) and transcription factor E2F are poorly activated, resulting in inefficient G1-to-S-phase progression. Furthermore, the absence of c-Jun results in elevated expression of the tumor suppressor gene p53 and its target gene, the CDK inhibitor p21, whereas overexpression of c-Jun represses p53 and p21 expression and accelerates cell proliferation. Surprisingly, protein stabilization, the common mechanism of p53 regulation, is not involved in up-regulation of p53 in c-jun-/- fibroblasts. Rather, c-Jun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter. Importantly, deletion of p53 abrogates all defects of cells lacking c-Jun in cell cycle progression, proliferation, immortalization, and activation of G1 CDKs and E2F. These results demonstrate that an essential, rate-limiting function of c-Jun in fibroblast proliferation is negative regulation of p53 expression, and establish a mechanistic link between c-Jun-dependent mitogenic signaling and cell-cycle regulation.
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PMID:Control of cell cycle progression by c-Jun is p53 dependent. 1007 88

Proliferating cell nuclear antigen (PCNA), also known as a cofactor of DNA polymerase delta, is required for eukaryotic cell DNA synthesis and nucleotide excision repair. Expression of PCNA gene is growth-regulated and UV inducible. In our previous study, we have observed that the rat PCNA promoter has the serum responsiveness. In this study, we demonstrate its UV inducibility in CHO.K1 cells. The UV induction of the rat PCNA promoter activity was dose-dependent in the cells synchronized at different phases. In addition, the sequences of the promoter responsible for the UV inducibility were delimited to the region between nucleotides -70 and +125, which contains an AP-1 site and a downstream proximal ATF/CRE site. While mutation of the AP-1 site abrogated the UV inducibility, mutation of the ATF/CRE site enhanced the UV inducibility, suggesting that the two sites play different roles in the UV induction of the promoter. In addition, the role of p53 in the UV induction of rat PCNA promoter was investigated. We found that exogenous p53 was unable to mimic the UV irradiation to induce rat PCNA promoter and that the UV induction of the rat PCNA promoter was seen in p53 deficient cells. Therefore, it is unlikely that the UV induction of the rat PCNA promoter is p53 dependent.
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PMID:UV inducibility of rat proliferating cell nuclear antigen gene promoter. 1032 41

Transcriptional control of p53 expression participates in the generation of appropriate levels of active p53 in response to mitogenic stimulation. This prompted us to study the role of a putative AP-1 and a NF-kappaB motif in the human p53 promoter for transcriptional regulation. We show that mutation of the AP-1 or the NF-kappaB motif abolishes transcription from the human p53 promoter in HeLa, HepG2 and adenovirus type 5 E1-transformed 293 cells. In comparison, mutation of the previously characterized Myc/Max/USF binding site in the human p53 promoter reduces the transcription rate fivefold. The AP-1 motif in the human p53 promoter binds c-Fos and c-Jun and the NF-kappaB motif binds p50(NF-kappaB) and p65RelA. The cooperative nature of transcriptional activation by these factors was documented by repression of c-fos or NF-kappaB1 translation: Pretreatment of the cells with a c-fos or p50(NF-kappaB1) antisense oligonucleotide suppresses transcription from the human p53 promoter completely. In addition, we show that (a) the level of endogenous p53 mRNA and (b) transcription from the strictly p53-dependent human mdm2 promoter are reduced in the presence of c-fos, c-jun, p50(NF-kappaB1), p65RelA or c-myc antisense oligonucleotides, underscoring the importance of these transcription factors for the expression of functional p53.
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PMID:Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-kappaB and Myc/Max. 1034 47

Apoptotic macrophages are regularly found in atherosclerotic plaques indicating programmed cell death as one of their regulatory controls. The objective of this study was to characterize in more detail apoptotic macrophages in atherosclerotic lesions of humans and heritable hyperlipidemic (HHL) rabbits. Macrophages were immunohistochemically analyzed using antibodies directed against alphaMbeta2-integrins (CD11b/CD18), CD44, major histocompatibility complex (MHC) class I and II, inducible nitric oxide synthase (iNOS), manganese superoxide dismutase (MnSOD), tumor necrosis factor alpha (TNFalpha), p53, c-jun/AP-1 and rabbit macrophages (RAM-11) and the TUNEL (TdT-mediated dUTP nick end labeling) technique. Colocalization studies of human atherosclerotic carotid and aortic tissue showed apoptotic plaque macrophages also being MnSOD-, alphaMbeta2-integrin-, CD44-, MHC class I- and II-, iNOS-, TNFalpha- and p53-immunoreactive. Similar results occurred in atherosclerotic aortas of HHL rabbits. Computer-assisted morphometric analyses revealed a positive correlation of the area density of MnSOD-immunoreactive macrophages with those of alphaMbeta2-integrin- and CD44-immunoreactive ones, but not with those of MHC class I- and II- as well as of RAM-11-immunoreactive macrophages. We conclude that apoptotic macrophages located in atherosclerotic vessel wall are activated, antigen-presenting, integrin-expressing and oxidatively stressed cells. Since all these processes have been demonstrated to cause apoptosis of macrophages in vitro, we propose their potency accelerates the susceptibility of the macrophages to programmed cell death in atherosclerotic lesions.
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PMID:Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits. 1038 Dec 75

The AP-1 transcription factor (the Jun and Fos proteins) is suspected of playing an important role in the biology of human cancer. Human epithelial ovarian tumors and cancer cell lines express the c-jun and jun-B proto-oncogenes at a high level, in contrast with the jun-D gene. We have investigated here the functional relevance of these observations for the growth of ovarian cancer cells. Transient constitutive expression of a dominant negative c-jun mutant (TAM67) in human AZ224, SKOV3 and OVCAR3 ovarian cancer cells inhibited the outgrowth of selection marker-resistant colonies by at least 75% as opposed to a control plasmid. Transfection of jun-B did not affect these cell lines, while jun-D transfection had a cell line-specific effect. In comparison, transfection of the tumor-suppressor gene p53 had a less important inhibitory effect on OVCAR3 cells and no effect on SKOV3 and AZ224 cells when compared to TAM67. Regulated TAM67 expression in AZ224 cells, from plasmids containing the mouse metallothionein or the MMTV promoter, suppressed cancer cell growth in vitro and in nude mice without evidence of increased cell death. Our observations support a role for the c-jun proto-oncogene as a positive mediator of human ovarian cancer cell growth and make it a potential therapeutic target.
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PMID:Alteration of jun proto-oncogene status by plasmid transfection affects growth of human ovarian cancer cells. 1041 66

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