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)

We wished to examine the role of transforming growth factor-beta (TGF-beta) in the regulation of human lymphoma cell growth. The RL cell line is an immunoglobulin M (IgM)+, IgD+ B lymphoma cell line, which does not constitutively express receptors for TGF-beta, and thus has lost the ability to respond to the inhibitory effects of TGF-beta. We demonstrate here that anti-Ig antibodies can efficiently upregulate the expression of TGF-beta receptors and promote sensitivity to growth inhibition by TGF-beta. Furthermore, because TGF-beta has been shown to function in late G1 of the cell cycle, we examined the ability of TGF-beta to modulate two tumor suppressor proteins known to be critical regulators of the G1/S transition, Rb and p53. Rb is a 105- to 110-kD phosphoprotein, which has been shown to maintain its growth suppressive function when it is found in the hypophosphorylated state. Wild-type p53 is a 53-kD phosphoprotein that appears to be important in preventing cell-cycle progression and promoting apoptosis in cells with DNA damage, whereas mutant p53 can overcome those functions. We show here that TGF-beta treatment of phorbol myristate acetate (PMA) or anti-Ig-activated RL cells results in growth inhibition through a dual effect on Rb and mutant p53. After TGF-beta treatment, we observe a predominance of Rb in the hypophosphorylated, growth suppressive form. In addition, we show a decrease in levels of mRNA and protein for mutant p53. We also show that, although these changes are sufficient to halt progression through the cell cycle, the cells do not appear to undergo extensive programmed cell death following 72 hours of TGF-beta treatment. Thus, although these lymphoma cells maintain the capacity to be negatively growth regulated by TGF-beta, the ability of TGF-beta to induce apoptosis must be independently controlled.
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PMID:Anti-IgM induces transforming growth factor-beta sensitivity in a human B-lymphoma cell line: inhibition of growth is associated with a downregulation of mutant p53. 772 77

Phospholipase C gamma-catalyzed inositol phospholipid hydrolysis, a critical step in B cell antigen receptor signaling leading to second messenger generation and proliferation, depends upon tyrosine kinase activation. The B cell antigen receptor-associated tyrosine kinases p53/56lyn, p59fyn, p55blk, and p72syk are assumed to participate in receptor-initiated signaling. It is unknown, however, which of these kinases is involved in the tyrosine phosphorylation and resulting activation of phospholipase C gamma in response to antigen receptor cross-linking. We have used a fusion protein containing the tandem src homology-2 (SH2) domains of phospholipase C gamma 1 (PLC gamma 1) to identify B cell kinases which associate with PLC gamma 1. Using an in vitro kinase assay, we demonstrate SH2-dependent association of tyrosine kinase activity from anti-mu-stimulated B cells. The PLC gamma 1 SH2 domains associate with a prominent 70-72-kDa tyrosine phosphoprotein from anti-mu-stimulated, but not resting, B cells. Immunoblotting and secondary immunoprecipitation studies definitively identify this protein as p72syk. These results imply a physical interaction between PLC gamma 1 and p72syk in antigen receptor-stimulated B cells. This conclusion is confirmed by our ability to co-immunoprecipitate p72syk and PLC gamma 1 from lysates of anti-mu-stimulated B cells. These results implicate p72syk in the activation of phospholipase C gamma 1 during B cell antigen receptor signaling.
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PMID:Association of p72syk with the src homology-2 (SH2) domains of PLC gamma 1 in B lymphocytes. 774 30

This study investigates whether a reciprocal association occurs between HPV infection and somatic mutation of the tumour suppressor gene p53 in laryngeal carcinomas. Using immunohistochemical techniques, 87 tumours were examined for expression of the mutant form of p53 phosphoprotein using the monoclonal antibody PAB 1801. The prevalence of different HPV types in these tumours was determined by using the polymerase chain reaction and restriction enzyme analysis. Over-expression of p53 was noted in 50/87 (57.5%) of the tumours investigated but not in any of the non-neoplastic laryngeal mucosa (controls). There was no statistical correlation between p53 immunoreactivity and the clinicopathological parameters of laryngeal carcinomas. HPV DNA was detected in 8/36 (22.2%) of the tumours: HPV-6 in three, HPV-11 in one, HPV-16 in two, and unknown HPV type in two. In p53-mutant tumours, HPV was present in 4/20 tumours but none of these were high risk HPV types. In p53-normal tumours, on the other hand, HPV was present in 4/16 tumours but two of these were definitely high risk HPV-16. These results imply the reciprocal association between HPV and somatic mutations of p53 found in the case of cervical carcinoma.
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PMID:The prevalence of different human papillomavirus types and p53 mutations in laryngeal carcinomas: is there a reciprocal relationship? 778

p53 is a nuclear phosphoprotein which acts as a tumour suppressor factor, regulating cell growth and division. Mutations in the p53 gene appear to be the most common genetic alterations in human cancer. The aim of this study was to investigate p53 expression in laryngeal squamous cell carcinomas and to assess its role as a marker of prognostic significance. Using immunohistochemical staining techniques, a series of laryngeal carcinomas (n = 87) were examined for expression of the mutant form of p53 phosphoprotein using the monoclonal antibody PAB 1801. p53 over-expression was noted in 50 biopsies of laryngeal carcinomas (57.5%) but not in any of the non-neoplastic laryngeal mucosa which were used as the control. There was no statistical correlation between p53 immunoreactivity and the clinicopathological parameters of the cancers including: site of tumour, TNM staging, differentiation grading and tumour recurrence. These findings indicate that p53 expression is strongly associated with carcinoma cells and not with normal cells in the larynx. However, p53 expression is probably unrelated to the biological aggressiveness of these tumours.
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PMID:Over-expression of tumour suppressor gene p53 in laryngeal squamous cell carcinomas and its prognostic significance. 778 34

The p53 encodes a cellular phosphoprotein that has been association with both neoplastic transformation and the control of cellular growth. Recent studies have reported that p53 also acts as a transcriptional regulator. We have studied transactivational properties of human wild-type and mutant p53 proteins representing 4 major mutational hotspots (codons 141, 175, 248, 273) as well as a double mutant Tyr141/His273 and a p53 with the transcriptional activating region removed (pcDC2). Transactivation by p53 was shown with a p53 concensus binding sequence controlled CAT reporter gene, and activity was assayed after co-transfection of the reporter with either wild-type or mutant p53 expression constructs. Wild-type p53 as well as one mutant p53 [(mutation of arginine to histidine at codon 273 (His 273)], had strong transactivating activity, but all other mutant p53s were inactive in transcriptional activation, including the double mutant Tyr141/His273 suggesting that the Tyr141 mutation was dominant over the His273 mutation in the same protein. Moreover, when mutant p53 (Tyr141, His175, Trp248, or Tyr141/His273) was cotransfected with either wild-type p53 or mutant His273 p53, these mutants inhibited the transactivation of coexpressed wild-type p53. The p53 vector (pcDC2), which contains p53 oligomerization sequences, but not the transactivational domain, markedly inhibited wild-type p53 transactivational activity. Each of the mutant p53s similarly inhibited the transactivation of His273 p53. Therefore, with the exception of His273, each of the other mutant p53 were unable to transactivate and each behaved in a dominant negative fashion.
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PMID:Mutant p53 proteins behave in a dominant, negative fashion in vivo. 784 18

The metastasis associated 18A2/mtsI gene was inserted into the mammalian expression vector pMAMneo placing it under the control of the dexamethasone-inducible MMTV promoter. The construct was transfected into dexamethasone receptor negative F1 and receptor positive F10 cells of the B16 murine melanoma. The transferred gene was switched on in two transfectant clones of F10, by exposure to 10(-6) M dexamethasone, but not in clones of the receptor negative F1 line. One of the F10 transfectant clones (F10-192/10) was characterized further. A 13.5-fold increase in 18A2/mts1 transcripts was found in this clone upon exposure to dexamethasone. There was also a seven-fold increase in lung colonization in an experimental metastasis assay, together with increased expression of depolymerized tubulin and enhanced detection of p53 protein. The number of cells in the S phase increased by 2.5-fold following dexamethasone treatment of the clone. These data suggest a direct involvement of the 18A2/mts1 gene in lung colonization by the tumor cells. The 18A2/mts1 protein promotes tubulin depolymerization, sequesters the p53 phosphoprotein, and induces the cells to enter the S phase, but the relevance of these in the metastatic process remains to be elucidated.
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PMID:Induction of 18A2/mts1 gene expression and its effects on metastasis and cell cycle control. 794 34

In this paper a multimarker immunohistochemical technique is described in detail which allows the quantitative evaluation in situ of cells expressing abnormal accumulation of p53 phosphoprotein together with the CD30 antigen, a well known marker of Hodgkin's and Reed-Sternberg cells. The method is useful to define quantitatively the proportion of phenotypically abnormal cells in the complex microenvironment of Hodgkin's lesions, and to compare the phenotypical derangement of p53 gene with molecular biology data obtained on the same samples.
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PMID:Quantitative approach to the immunohistochemical analysis of p53 antioncogene and CD30 antigen in Hodgkin' disease. 821 85

The p53 gene, which is frequently mutated in various tumors, encodes a phosphoprotein thought to have a key role in the regulation of cell proliferation. To explore their biological effects, the HeLa carcinoma line, which does not express p53, was co-transfected with plasmid constructs expressing wild-type or mutant p53 proteins, or unrelated proteins, along with a plasmid conferring resistance to a neomycin-kanamycin antibiotic analog (G418). Both wild-type and mutant forms of p53 stimulated the number of G418-resistant colonies between 5- and 36-fold. Further investigation of colony development revealed that p53 enhanced cell survival, leading to increased colony numbers, but did not stimulate cell growth. Nonetheless, we suggest that an initial slowing of cell growth caused by expression of the unintegrated p53 plasmids renders the transfectants resistant to selection with G418, thus causing a higher frequency of G418-resistant colonies. p53 constructs were found to be expressed transiently in HeLa cells as expected, but the G418-resistant colonies frequently failed to express p53. This loss of p53 expression may be due to negative regulatory effects of p53 on the cytomegalovirus promoter that drives the selection marker.
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PMID:p53 confers a selective advantage on transfected HeLa cells. 845 34

We have studied the role of the retinoblastoma susceptibility gene product (pRB) in the regulation of cell-cycle progression under extremely hypoxic conditions (< 4 ppm O2). pRB is a nuclear matrix-associated phosphoprotein that normally exerts its growth-regulatory effects during early-G1 phase of the cell cycle, where all pRB present has been assumed to be in the under-phosphorylated form and bound in the nucleus. The effect of hypoxia on pRB nuclear binding and its state of phosphorylation was studied by two methods: (a) two-parametric flow cytometric measurement of pRB versus DNA and (b) Western blotting. Pulse-chase and pulse labeling with BrdUrd was used to record cell-cycle progression under versus after extremely hypoxic conditions. We demonstrate that pRB is dephosphorylated and rebound in the nucleus in more than 90% of cells located in S and G2 under extremely hypoxic conditions. While inhibition of DNA synthesis was instantaneous under hypoxic conditions, dephosphorylation and rebinding to nuclear structures of pRB takes more than 4 h. Within this time span, cells in G2 complete mitosis and divide. The slow dephosphorylation of pRB indicates that pRB is neither associated with the instantaneous inhibition of DNA synthesis nor is it the cause of the oxygen-dependent restriction point located in late-G1. The observed dephosphorylation of pRB is not dependent on functional p53, suggesting that at least one of the mechanisms responsible for the dephosphorylation is due to hypoxic activation of a pRB-specific phosphatase in the absence of p53-dependent inhibition of pRB kinase activity. However, it cannot be ruled out the participation of pRB kinase inhibitors independent of p53 activation. Cells arrested in G1 during prolonged hypoxia resumed cell-cycle progression within 2-->24 h after reoxygenation, while cells arrested in S were unable to reenter cell-cycle progression after reoxygenation. The hypoxia-induced dephosphorylation of pRB was only partly reversible by reoxygenation. Reentry into the cell cycle induced by reoxygenation occurred concomitant with unbinding (hyperphosphorylation) of pRB. Thus, rephosphorylation of pRB seem to be the rate-limiting step for reentry into the cell cycle after reoxygenation. Although pRB seems to play a major role in suppression of cell growth under and following hypoxic stress, other factors seem to be responsible for the immediate hypoxia-induced arrest in late-G1 and S phases.
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PMID:The retinoblastoma gene product is reversibly dephosphorylated and bound in the nucleus in S and G2 phases during hypoxic stress. 880 57

Previous studies have identified a 180-kDa mouse cardiomyocyte phosphoprotein with limited epitopic homology to p53. In this study, the protein was purified and partially sequenced. Oligonucleotide probes based on the available amino acid sequence data were used to isolate cDNA clones. Sequence analyses revealed that the clones encoded a protein with regional homology to the yeast RAD50 gene product. Expression of the mouse cDNA rescued the methyl methanesulfonate-sensitive phenotype in rad50 mutant yeast, indicating that the cardiomyocyte phosphoprotein is the mammalian homologue of the yeast RAD50 gene product. Fluorescence in situ hybridization analyses localized the mouse RAD50 gene to the A5-B1 region of chromosome 11. Northern blot analyses demonstrated a complex pattern of RAD50 expression during mouse development which was further complicated by the presence of several alternatively spliced transcripts. High levels of RAD50 expression was evident in the adult myocardium, a somewhat surprising observation given the absence of DNA synthesis in adult cardiomyocytes.
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PMID:Mouse RAD50 has limited epitopic homology to p53 and is expressed in the adult myocardium. 891 May 85


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