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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 is currently considered to function as a tumor-suppressor gene in various human malignancies. In hematologic malignancies, alterations in the p53 gene have been shown in some human leukemias and lymphomas. Although mutations in the p53 gene are infrequent in acute myelogenous leukemia (AML) patients, we show in this report that alterations in the p53 gene are frequent in myeloid leukemia cell lines. We studied alterations of the p53 gene in nine human myeloid leukemia cell lines by reverse transcriptase-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and direct sequencing. Expression of the p53 gene was not detected at all by RT-PCR in two of the nine cell lines. In these two cell lines, Southern blot analysis showed gross rearrangements and deletions in both of the p53 alleles. Six of the nine cell lines were found to express only mutant p53 mRNA by RT-PCR/SSCP analysis and direct sequencing, and wild-type p53 mRNA was not detected. Two of the mutant p53 mRNAs were shown to be products of abnormal splicing events induced by intronic point mutations. Taken together, eight of nine human myeloid leukemia cell lines expressed no or an undetectable amount of wild-type p53 mRNA. Three of the eight cell lines were growth factor-dependent. Our results suggest that inactivation of the p53 gene may be a common feature in myeloid leukemia cell lines and may play an important role in the establishment of these cell lines.
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PMID:Frequent mutations in the p53 gene in human myeloid leukemia cell lines. 157 49

Ultrastructural, flow cytometric, and molecular studies were performed on leukemia cells from bone marrow and pleural effusion of a 6-year-old boy diagnosed with undifferentiated (MO) leukemia, using routine histology and immunostains at diagnosis and relapse. Ultrastructurally, surface and/or intracellular ferritin particles were present on or in some blasts and the majority of blasts contained identifiable acid ferrocyanide reactive inorganic iron comparable to that seen in normal early erythroblasts. The cells lacked other evidence of differentiation, including diaminobenzidine-reactive or immunoreactive hemoglobin. Flow cytometric analysis of malignant cells showed a lack of lymphoid or myeloid markers. Anti-transferrin receptor antibody was positive on 93% of cells and antibody to glycophorin A reacted with 23% of cells. RNA blot analysis of leukemia cells with myeloperoxidase (MPO) showed an absence of appreciable levels of MPO mRNA. Chromosome analysis showed 51,XY, t(1;16)(p31;q24), +6, +10, +15, +19, +21. The oncogene c-myb, which is specifically expressed and regulated in hematopoietic cells and produces a DNA-binding protein responsible for myeloid differentiation, was found to be duplicated in the patient's tumor cells. Expression of c-jun, N-ras, c-myc, and p53 was normal. The data indicate that the malignant cells in this patient are of early erythroid lineage at diagnosis and relapse and that classification of cell lineage can be enhanced by ultrastructural Prussian blue staining. The failure of this otherwise undifferentiated leukemia to express or evolve into a myeloid phenotype is biologically and clinically distinct from previously described cases of erythroid and myeloid leukemia and may represent a previously unidentified phenotype which should be included in the spectrum of 'undifferentiated' childhood leukemia.
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PMID:Childhood undifferentiated leukemia with early erythroid markers and c-myb duplication. 170 34

Expression of p53 oncogene in blast cells may have prognostic importance in acute leukemia. Simple and reliable methods which could detect enhanced p53 expression in leukemia cells would be important for follow-up studies of leukemia patients in remission. We used immunoperoxidase (IP) technique with an anti-p53 monoclonal antibody PAb421 to study the expression of p53 in leukemia cells. The expression of p53 was studied in 9 cell lines and 17 de novo acute leukemia (9 acute myeloid leukemia [AML], 8 acute lymphoblastic leukemia [ALL]) patients. The expression of p53 was demonstrated in non-T non-B cells and Burkitt's lymphoma cell lines, but neither in two myeloid leukemia cell lines nor in normal lymphoid cells after mitogenic stimulation. p53 expression was demonstrated in 7 cases (2 AML, 5 ALL) but only in ALL cases the percentage of positive of cells was over 20%. Bone marrow cells from patients were studied also after short-term culture (AML patients); in 1 case the number of PAb421-positive cells rose significantly after culture. These data suggest that IP staining with PAb421 can be used to demonstrate high p53 expression in B cell leukemias.
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PMID:Detection of p53 oncogene in acute-leukemia cells by immunoperoxidase technique. 185 83

The expression of 20 proto-oncogenes was analysed by Northern blotting in four cell lines derived from patients with Hodgkin's disease (L428, L540, CO and DEV) and compared to lymphoid and myeloid leukemia cell lines and normal hematopoietic cells. Expression of the proto-oncogenes c-myc, p53, c-jun, pim-1, lck, c-syn, c-raf and N-ras were detected in Hodgkin's disease derived cell lines and in normal hematopoietic cells. Transcripts of the proto-oncogene c-met were detected in the Hodgkin's derived cell lines L428 and L540 but not in the lymphoid or myeloid leukemia cell lines or in tonsil cells, peripheral blood mononuclear cells and granulocytes. Expression of the proto-oncogenes N-myc and lck were observed in the Hodgkin's derived cell line CO which express T cell receptor genes and in the T cell lines JM and CEM. L428 cells and CO cells expressed aberrant transcripts of the c-fes proto-oncogene. Thus Hodgkin's disease derived cell lines are heterogeneous in their expression pattern of proto-oncogenes, expressing normal and aberrant transcripts of proto-oncogenes which are not found in untransformed hematopoietic cells.
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PMID:Heterogeneous expression of proto-oncogenes in Hodgkin's disease derived cell lines. 221 Jun 88

We examined synthesis of the cellular phosphoprotein p53 in fresh bone marrow or peripheral blood cells from normal donors and from patients with leukemia, preleukemia, or other hematopoietic disorders. Lysates of cells labeled with [35S]methionine were immunoprecipitated with monoclonal antibodies to p53, and the immunoprecipitates were analyzed by NaDodSO4/polyacrylamide gel electrophoresis and autoradiography. Bone marrow or peripheral blood cells from 8 of 33 patients with hematopoietic disorders showed increased p53, seven of the eight occurring in cells of patients with preleukemia or acute myelogenous leukemia. Increased p53 synthesis was not associated with p53 gene amplification, as shown by Southern blot analysis. Synthesis of p53 was not increased in any of nine normal human bone marrow samples or eight normal human peripheral blood granulocyte, macrophage, and lymphocyte samples. The hematopoietic cells of patients in remission or with chronic forms of leukemia did not generally synthesize elevated levels of p53. In addition, we found negligible p53 mRNA and protein expression in a variety of human myeloid leukemia lines blocked at different stages of differentiation. Southern blot analysis showed that, except for the HL-60 cells, the p53 gene of the myeloid cell lines was intact. In view of recent evidence implicating p53 in transformation of cultured cells, our results using fresh leukemia cells suggest that p53 may contribute to the phenotype of certain leukemias in vivo.
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PMID:Increased expression of p53 protein in human leukemia cells. 301 45

TNF-alpha is a pleiotropic cytokine with stimulatory as well as inhibitory effects on hematopoiesis. We have previously demonstrated that TNF-alpha directly inhibits CSF-induced proliferation of primitive murine lineage-negative bone marrow progenitors (Lin-) and stem cell antigen-1 hematopoietic progenitors through the 75-kDa TNF receptor (TNF-R2), whereas TNF-alpha-induced inhibition of more committed Lin- progenitors is mediated through the 55-kDa TNF-R (TNF-R1), indicating a differential role of the two TNF-Rs in hematopoiesis. Numerous studies have demonstrated the ability of stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, to synergize with other hematopoietic growth factors, but little is known about cytokines capable of inhibiting hematopoiesis induced by SCF. While TNF-alpha has been demonstrated to enhance SCF-induced proliferation of myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by signaling through TNF-R2, inhibits SCF-induced proliferation of normal murine Lin- and stem cell antigen-1 hematopoietic progenitors. SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also potently inhibited by TNF-alpha and was accompanied by down-regulation of c-kit cell surface expression as well as c-kit mRNA levels. Finally, treatment of the FDC-P1 cell line with TNF-alpha resulted in increased levels of the tumor suppressor p53 mRNA, suggesting another mechanism by which hematopoietic effects of TNF-alpha may be mediated.
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PMID:Inhibition of stem cell factor-induced proliferation of primitive murine hematopoietic progenitor cells signaled through the 75-kilodalton tumor necrosis factor receptor. Regulation of c-kit and p53 expression. 753 12

Altered p53 tumor suppressor genes have been described in various human malignancies, including in chronic myelogenous leukemias (CML) and acute myelogenous leukemias (AML), as well as their derivative cell lines. It has been proposed that this gene mutation may be less frequent in myeloid leukemia patients than in myeloid leukemia cells lines and that the latter acquire these mutations during growth in vitro. We investigated this possibility by studying p53 gene alterations in matched samples of fresh leukemic cells and their respective derivative cell lines obtained from two CML blast crisis and one AML patient. No gross structural abnormalities were detected in the p53 gene in any of the samples analyzed. Discrete mutations in the gene in the two CML blast crisis samples and in all three derivative cell lines were, however, detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analyses and DNA sequencing. Cytogenetic analyses revealed either numerical or structural, as well as numerical, abnormalities of chromosome 17 in their karyotypes. Cells from the two CML blast crisis patients had two different mutations which were maintained as the sole mutations in the cell lines. The mutation detected in the AML cell line was, however, not detectable in the parental fresh leukemic cells. Our findings demonstrate that p53 mutations and chromosome 17 abnormalities occurring in CML blast crisis patients persist in long-term cell lines but that mutations not detectable in AML patients may indeed be acquired in cell lines established from them in vitro.
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PMID:p53 gene mutations with chromosome 17 abnormalities in chronic myelogenous leukemia blast crisis patients persist in long-term cell lines but may be acquired in acute myeloid leukemia cells in vitro. 762 32

The tumor suppressor p53 is a cell cycle checkpoint protein that contributes to the preservation of genetic stability by mediating either a G1 arrest or apoptosis in response to DNA damage. Recent reports suggest that p53 causes growth arrest through transcriptional activation of the cyclin-dependent kinase (Cdk)-inhibitor Cip1. Here, we characterize the p53-dependent G1 arrest in several normal human diploid fibroblast (NDF) strains and p53-deficient cell lines treated with 0.1-6 Gy gamma radiation. DNA damage and cell cycle progression analyses showed that NDF entered a prolonged arrest state resembling senescence, even at low doses of radiation. This contrasts with the view that p53 ensures genetic stability by inducing a transient arrest to enable repair of DNA damage, as reported for some myeloid leukemia lines. Gamma radiation administered in early to mid-, but not late, G1 induced the arrest, suggesting that the p53 checkpoint is only active in G1 until cells commit to enter S phase at the G1 restriction point. A log-linear plot of the fraction of irradiated G0 cells able to enter S phase as a function of dose is consistent with single-hit kinetics. Cytogenetic analyses combined with radiation dosage data indicate that only one or a small number of unrepaired DNA breaks may be sufficient to cause arrest. The arrest also correlated with long-term elevations of p53 protein, Cip1 mRNA, and Cip1 protein. We propose that p53 helps maintain genetic stability in NDF by mediating a permanent cell cycle arrest through long-term induction of Cip1 when low amounts of unrepaired DNA damage are present in G1 before the restriction point.
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PMID:DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. 795 16

Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli. We have used M1 myeloid leukemia cells and genetically engineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by activation of wild type p53 function of a temperature sensitive p53 transgene expressed in M1 cells, which do not express endogenous p53, and apoptosis induced by TGF beta 1. It is shown that the kinetics of apoptosis induced by p53 is more rapid than apoptosis induced by TGF beta 1. It is also shown that ectopic expression of Bcl-2, at levels which blocked TGF beta 1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGF beta 1 down-regulated endogenous Bcl-2 expression, but only p53 up-regulated Bax expression, where bax has been identified as a p53 immediate early response gene. Thus, the p53-mediated up-regulation of Bax may provide at least a partial explanation for the more rapid rate of apoptosis induced by p53 compared to by TGF beta 1, as well as for the ineffectiveness of ectopoic Bcl-2 to abrogate p53-mediated apoptosis. These findings provide first insights to the molecular mechanisms which mediate p53-induced apoptosis, identifying bax and bcl-2 as p53 regulated genes, and serve as a paradigm of how the intracellular balance of Bcl-2 to Bax is differentially altered by distinct death stimuli.
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PMID:Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. 818 78

Stable transfection of M1 myeloid leukemia cells with a temperature-sensitive mutant of p53 results in two phenomena that are manifested exclusively at the permissive temperature. On one hand, activation of wild-type p53 by the temperature shift induced an apoptotic type of cell death which could be inhibited by interleukin-6 (IL-6) (E. Yonish-Rouach, D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Nature 352:345-347, 1991). On the other hand, as reported in this work, activated p53 complemented the antiproliferative effects of IL-6 in M1 cells. A shift to the permissive temperature concomitant with or early after IL-6 treatment imposed a novel pattern of cell cycle arrest in which about 95% of the cells were retained within a G0-like quiescent state. This phase was characterized by 2N DNA content and low RNA and protein content. On the molecular level, activation of wild-type p53 transrepressed the c-myc gene but not the cyclin A, D1, or D2 gene, which are all independently suppressed by IL-6 in M1 cells. To further analyze whether c-myc inhibition mediates or complements p53 effects, the p53-transfected M1 cells were infected with a retroviral vector expressing deregulated c-myc, refractory to p53 or IL-6 action. It was found that the process of cell death was not interrupted at all in these M1 c-myc-p53 double transfectants, suggesting that the transrepression of c-myc is not a major obligatory event mediating p53-induced cell death. In addition, some of the antiproliferative effects of activated p53, manifested in the presence of IL-6, could still be transmitted in the background of constitutive c-myc. Yet the context of deregulated c-myc interfered with the final accumulation of cells within a G0-like phase, suggesting complementary interactions between the outcome of p53 activation and of c-myc suppression in the control of cell cycle arrest.
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PMID:Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression. 824 9


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