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)

Eighty monoclonal antibodies (MAbs) against parainfluenza virus type 4(PIV-4) were isolated and characterized. Of 50 MAbs against PIV-4A, 14 reacted with the nucleocapsid (NP) protein, 11 with the hemagglutinin-neuraminidase (HN) glycoprotein, 6 with the fusion (F) glycoprotein, and 19 with the matrix (M) protein. With the aid of the PIV-4A and PIV-2 specific MAbs showing cross-reactivity with PIV-4B, the structural proteins of PIV-4B were identified. gp72, p65, gp65, gp55, p53, and p40 of PIV-4B were assigned to HN, NP, Fo, F1, P, and M proteins, respectively. Based on the results, specificities of the MAbs against PIV-4B were determined. Of 30 hybridoma clones against PIV-4B, 13 clones were found to produce antibodies against the NP protein, 7 against the HN protein, and 10 against the F protein. Epitope mapping of these MAbs was performed with competitive binding assays in ELISA. According to their biological activities, the MAbs against the HN protein of either PIV-4A or 4B could be divided into three groups. The first group showed high hemagglutination inhibition (HI), hemolysis inhibition (HLI), and neutralizing (NT) activities. The second group showed high NT activity, but could not block hemagglutination. The final group showed a lower level of all activities. The MAbs against the F protein of PIV-4A and against PIV-4B were divided into two groups. Some MAbs against the F protein had high titer of NT, suggesting that the F protein had neutralizing-related epitopes. Antigenicity of the NP protein was highly conserved among subtypes of PIV-4. On the other hand, the MAbs against the HN and the F proteins showed high reactivity with the homologous subtype viruses, but low reactivity with the heterologous subtype viruses, indicating that the external glycoproteins exhibited antigenic variations between two subtypes of PIV-4. When the immunological interrelationship among various paramyxoviruses was analyzed. PIV-4 was found to be antigenically related to PIV-2, SV 5, and mumps virus.
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PMID:Isolation and characterization of monoclonal antibodies to human parainfluenza virus type 4 and their use in revealing antigenic relation between subtypes 4A and 4B. 247 3

p53 is recruited in response to DNA-damaging genotoxic stress and plays an important role in maintaining the integrity of the genome. We show that exposure of cells to various genotoxic agents, including anticancer drugs such as mitomycin and 5-fluorouracil, results in an increase in p53 mRNA levels and in p53 promoter activation, indicating that the p53 genotoxic stress response is partly regulated at the transcriptional level. The results of the p53 promoter analysis show that a novel p53 promoter element, termed a p53 core promoter element (from -70 to -46), is essential for basal p53 promoter activity and promoter activation induced by genotoxic agents such as anticancer drugs and UV. Although a kappa B motif partially overlaps with this element and those genotoxic agents activate NF-kappa B, it does not play a major role in p53 genotoxic stress response: NF-kappa B p65 expression did not induce significant p53 promoter activation, and NF-kappa B inhibitors (N-acetyl cysteine and I kappa B alpha) did not inhibit genotoxic stress-inducible p53 promoter activation. Finally, we characterized nuclear factors, the binding of which to the p53 core promoter element is essential for basal p53 promoter activity and p53 promoter activation induced by genotoxic agents.
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PMID:Identification of a novel p53 promoter element involved in genotoxic stress-inducible p53 gene expression. 762 39

In most cases, the transcriptional factor NF-kappa B is a heterodimer consisting of two subunits, p50 and p65, which are encoded by two distinct genes of the Rel family. p50 is translated as a precursor of 105 kDa. The C-terminal domain of the precursor is rapidly degraded, forming the mature p50 subunit consisted of the N-terminal region of the molecule. The mechanism of generation of p50 is not known. It has been suggested that the ubiquitin-proteasome system is involved in the process; however, the specific enzymes involved and the mechanism of limited proteolysis, in which half of the molecule is spared, have been obscure. Palombella and colleagues (Palombella, V. J., Rando, O. J., Goldberg, A. L., and Maniatis, T. (1994) Cell 78, 773-785) have shown that ubiquitin is required for the processing in a cell-free system of a truncated, artificially constructed, 60-kDa precursor. They have also shown that proteasome inhibitors block the processing both in vitro and in vivo. In this study, we demonstrate reconstitution of a cell-free processing system and demonstrate directly that: (a) the ubiquitin-proteasome system is involved in processing of the intact p105 precursor, (b) conjugation of ubiquitin to the precursor is an essential intermediate step in the processing, (c) the recently discovered novel species of the ubiquitin-carrier protein, E2-F1, that is involved in the conjugation and degradation of p53, is also required for the limited processing of the p105 precursor, and (d) a novel, approximately 320-kDa species of ubiquitin-protein ligase, is involved in the process. This novel enzyme is distinct from E6-AP, the p53-conjugating ligase, and from E3 alpha, the "N-end rule" ligase.
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PMID:Ubiquitin-mediated processing of NF-kappa B transcriptional activator precursor p105. Reconstitution of a cell-free system and identification of the ubiquitin-carrier protein, E2, and a novel ubiquitin-protein ligase, E3, involved in conjugation. 766 88

The tumor suppressor p53 is a potent transcriptional activator that has been shown to regulate its own expression. In earlier studies, deletion analysis and site-specific mutagenesis identified the p53-responsive element that fits the p53 consensus sequence. In addition, the p53-responsive element was predicted to be a binding site for NF-kappa B. In this study, we showed that NF-kappa B present in HeLa nuclear extracts could bind the same DNA element in a sequence-specific manner. Co-transfection experiments showed that the p65 subunit of NF-kappa B, but not the p50 subunit, could activate the p53 promoter. In HeLa cells, tumor necrosis factor alpha (TNF-alpha) induced NF-kappa B activity. The p53 promoter was also induced by TNF-alpha under the same conditions. Both p65 transactivation and TNF-alpha induction of the p53 promoter depended on an intact NF-kappa B site. Detailed mutational analysis of the p53 and NF-kappa B responsive elements allowed differentiation of these two responses. Thus, we show that NF-kappa B activates p53 and that this activation is inducible by TNF-alpha. Since NF-kappa B induction occurs as a response to stress and p53 arrests cells in G1/S, where repair may be initiated, activation of p53 by NF-kappa B could be a mechanism by which cells can recover from stress.
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PMID:NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. 805 Oct 93

The antioxidant alpha-tocopherol and the weaker antioxidant and prooxidant chemopreventative, beta-carotene have been shown to inhibit tumor cell growth in vivo and in vitro. In some epidemiologic studies their serum levels were demonstrated to be inversely related to the incidence of malignant tumor. We hypothesized two basic pathways triggered by antioxidants and prooxidants, which resulted in the control of tumor cell growth. These included changes in phosphorylation and ultimately transcription. Specifically, the prooxidant beta-carotene treatment produced an oxidative stress resulting in the selective induction of heat shock proteins (hsps). These proteins and other proteins that were possibly oxidized were associated with the increased expression of cyclins (A and D) and increased cdc2 kinase expression. An increase in expression of phosphoproteins, such as p53 (tumor suppressor form) was also discerned. The level of expression for the transcription factor c-fos was reduced. Growth factors that contribute to tumor cell growth were also reduced. Increased DNA fragmentation, depression of proliferation and intracellular calcium levels, the accumulation of tumor cells in G0-->G1, and morphologic changes, were consistent with programmed cell death. Antioxidants such as alpha-tocopherol bound to membrane-associated proteins could inhibit the development of peroxidation products (hydroxyl radicals (.OH)), which attack proteins and modify their function and promote their degradation. Some kinases such as, cdc2 may be increased in activity, which would explain the observed increased expression of tumor suppressor p53, the accumulation of the tumor cells in G1 of the cell cycle and the inhibition of tumor cell proliferation. A reduction in oxidant radicals could also reduce transcription factor products, such as c-myb. Indirectly this result may occur through changes in nuclear translocation (signaling) NF-AT or the Rel-related family of transcription factors, including NF-kB (p50 or p65) or inhibition of immunophilin-calmodulin activity. Although the data remains fragmentary there are common points for control for tumor cell growth resulting from the effects of alpha-tocopherol or beta-carotene treatment. These changes involve phosphorylation and protein expression. Ultimately there is a reduction of important transcription factor protein products, a reduction in response to growth factors, and suppression of cell proliferation, resulting in increased control of the cell cycle.
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PMID:Molecular and biochemical reprogramming of oncogenesis through the activity of prooxidants and antioxidants. 851 52

Among the many target genes of the transcription factor NF-kappaB are p53 and c-myc, both of which are involved in apoptosis. This prompted us to investigate the role of NF-kappaB in this process. We report that NF-kappaB is potently activated upon serum starvation, a condition leading to apoptosis in 293 cells. Similar to Bcl-2, a transdominant-negative mutant of the NF-kappaB p65 subunit partially inhibited apoptosis, indicating a direct involvement of the transcription factor in induction of cell death. As expected, the p65 mutant suppresses kappaB-dependent gene expression. Surprisingly, transiently or stably overexpressed Bcl-2 had the same effect. The transcription inhibitory activity of the two proteins correlated with their cell death protective potential. Like Bcl-2, the related protein Bcl-xL but not Bcl-xS was able to suppress kB-dependent transcription. Bcl-2 inhibited NF-kappaB activity by an unusual mechanism. It did not prevent the release of IkappaB in the cytoplasm but down-modulated the transactivating potential of nuclear p65. These data show that NF-kappaB can participate in apoptosis. We suggest that at least part of the anti-apoptotic potential of Bcl-2 may be explained from a hitherto undiscovered activity of Bcl-2 in controlling nuclear gene expression.
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PMID:Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis. 869 9

p202, an interferon-inducible murine protein, is a member of the "200 family" of proteins and is primarily nuclear. p202 is a modulator of transcription; it binds several transcription factors, including NF-kappaB p50 and p65, AP-1 c-Fos and c-Jun, and E2F1, and inhibits their transcriptional activity. p202 also binds pRb, the retinoblastoma protein, and if overexpressed it retards cell proliferation. Here we report that using the yeast two-hybrid assay we found that p202 bound the murine homolog of the human p53-binding protein 1 (53BP1), a protein shown to interact with the DNA binding domain of the p53 tumor suppressor protein. p202 bound a 98amino acid segment from 53BP1. This binding was inhibited by the replacement in p202 of a histidine (from the M(F/L)HATVA(T/S) sequence that is conserved among all of the 200 family proteins) by phenylalanine. We also report that overexpression of p202 inhibited the p53-dependent expression of reporter genes containing p53-activable segments from the mdm2 and p21 genes, whereas a decrease in the p202 level (in consequence of the expression of 202 antisense RNA) resulted in an increase in the p53-dependent expression of these reporters. Expression of the 53BP1 segment binding to p202 overcame the inhibition by overexpressed p202 of the transcription of reporters mediated by the p53 or the AP-1 transcription factors and of the proliferation of yeast.
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PMID:p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. 891 Mar 40

The general transcription initiation factor TFIID contains the TATA-binding protein (TBP) and TBP-associated factors (TAFs) implicated in the function of gene-specific activators. Previous studies have indicated that a hamster cell line (ts13) with a point mutation in the TAF(II)250/CCG1 (TAF(II)250) gene shows temperature-sensitive expression of a subset of genes and arrests in late G1 at 39.5 degrees C. Here, we report the identification of cell cycle-specific (G1-specific) genes that appear to be regulated directly through TAF(II)250 both in vivo and in vitro. Transcription rates of several cell cycle-regulatory genes were determined by run-on assays in nuclei from ts13 cells grown at permissive (33 degrees C) and nonpermissive (39.5 degrees C) temperatures. Temperature-dependent differences in transcription rates were observed for cyclin A, D1, and D3 genes. In transient-transfection assays, the human cyclin D1 promoter fused to a luciferase reporter showed a temperature-dependent reduction in activity in ts13 cells but not in parental BHK cells. In in vitro assays, upstream sequence-dependent transcription from the human cyclin D1 promoter was significantly reduced in ts13 nuclear extracts preincubated at 30 degrees C but not in similarly treated BHK nuclear extracts, and transcription in the ts13 extract was restored by addition of an affinity-purified human TFIID. Preincubation of the ts13 nuclear extracts did not affect the function of several GAL4-activation domain fusion proteins (GAL4-VP16, GAL4-p65, and GAL4-p53) on either the adenovirus major late or cyclin D1 core promoter bearing GAL4 sites, further indicating that the effect of the TAF(II)250 mutation is both core promoter and activator specific.
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PMID:The ts13 mutation in the TAF(II)250 subunit (CCG1) of TFIID directly affects transcription of D-type cyclin genes in cells arrested in G1 at the nonpermissive temperature. 915 27

Cisplatin exposure induces apoptosis in HeLa cells. Since the interaction of this drug with DNA produces reactive oxygen species, we performed an analysis of the oxidative stress-responsive factors AP-1 and NF-kappa B. Although AP-1 levels were not modified during cisplatin exposure, electrophoretic mobility shift assays demonstrated an increase in NF-kappa B DNA binding activity that correlated with a decrease of the inhibitory protein I kappa B alpha and a specific relocalization of c-Rel, as assessed by immunoblotting and immunofluorescence. No changes in the levels or localization of p65 were found. Interestingly, I kappa B alpha relocalized to the nucleus, probably in order to regulate the binding of specific complexes. This process was accompanied by a decrease of the antiapoptotic protein Bcl-2, and a relocalization of p53 protein to the nucleus. Since HeLa cells lost most of their p53 protein due to a specific E6-dependent degradation, cisplatin could be inhibiting this degradation, since the p53 total levels were not increased during the exposure to the drug.
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PMID:Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa cells. 940 32

Normal fibroblasts are resistant to the cytotoxic action of tumor necrosis factor (TNF), but are rendered TNF-sensitive upon deregulation of c-Myc. To assess if oncoproteins induce the cytotoxic TNF activity by modulating TNF signaling, we investigated the TNF-elicited signaling responses in fibroblasts containing a conditionally active c-Myc protein. In association with cell death, c-Myc impaired TNF-induced activation of phospholipase A2, JNK protein kinase and cell survival-signaling-associated NF-kappaB transcription factor complex. The TNF-induced death of mouse primary fibroblasts expressing deregulated c-Myc was inhibited by transient overexpression of the p65 subunit of NF-kappaB, which increased NF-kappaB activity in the cells. Unlike other TNF-induced signals, TNF-induced accumulation of the wild-type p53 mRNA and protein was not inhibited by c-Myc. TNF, with c-Myc, induced apoptosis in mouse primary fibroblasts but only weakly in p53-deficient primary fibroblasts. The C-terminal domain of p53, which is a transacting dominant inhibitor of wild-type p53, failed to inhibit apoptosis by c-Myc and TNF, suggesting that the cell death was not dependent on the transcription-activating function of p53. Taken together, the present findings show that the cytotoxic activity of TNF towards oncoprotein-expressing cells involves p53 and an impaired signaling for survival in such cells.
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PMID:Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappaB activation. 940 67


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