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)

The multistep nature of human cancers is well illustrated by chronic myelogenous leukemia (CML), a clonal hematologic malignancy with two distinct phases: chronic and acute. Transition between these phases is characterized by unregulated growth and loss of differentiation of myeloid cells and their progenitors. We recently reported that loss of normal p53 expression correlates with transition from the chronic to acute phase in at least 25% of cases of CML. However, the precise relationship between this loss and biologic features of acute-phase CML is uncertain. To study this question, we artificially expressed normal p53 in K562, an erythroid acute-phase CML cell line lacking normal p53 expression. Biological effects were assessed by determining several growth parameters and by measuring synthesis of hemoglobin, a feature of mature erythroid cells. K562 cells expressing normal p53 had an increased proportion of cells in G1 versus S + G2, a longer doubling time and a lower growth saturation density than control K562 cells or K562 cells with antisense p53. Cells with normal p53 also expressed up to 50-fold more hemoglobin than controls. These data are consistent with the notion that loss of p53 expression may be responsible for many of the features of acute-phase CML cells. The data also demonstrate direct involvement of p53 in differentiation processes.
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PMID:Expression of the normal p53 gene induces differentiation of K562 cells. 150 93

The development of Friend virus induced murine erythroleukaemia is associated with specific genetic events. One of these events is loss of wild type p53 expression, which can occur by internal deletion or proviral insertion in the p53 gene and by single point mutations in the coding sequence. In all cases, the corresponding wild type allele is absent. The high frequency of observed p53 mutations strongly suggests that inactivation of p53 may be an obligatory step in the development of Friend disease. Further evidence that abrogation of normal p53 expression contributes to the development of malignant clones was provided by in vitro reconstitution experiments in Friend cell lines: whereas exogenous mutant p53 was stably expressed in p53 negative FCLs, long term wild type p53 expression was not detected. Friend erythroleukaemia arises as a late consequence of infection of susceptible mice with Friend virus. In addition to p53 gene mutations, proviral insertions occur frequently adjacent to one of two cellular genes, Spi-1/PU.1 or Fli-1. Aberrant expression of these genes may therefore be involved in virus induced erythroleukaemia. Interaction of SFFV env gp55 with the EPO-R also appears to be important in providing a mitogenic signal to infected cells. The order in which these events occur and whether the order is relevant to the progression of the disease are not known. Investigation of the stepwise appearance of these events could provide information on the possible interactions of the gene products involved. Abrogation of normal p53 expression is not restricted to Friend erythroleukaemia: the observation of p53 mutations and allele loss in human breast, lung, colon and hepatocellular carcinomas and in leukaemia suggests that mutation of p53 may be the most common genetic abnormality detected in human cancer (reviewed in this issue). Studies of p53 expression in FCLs provided an early indication that p53 was a tumour suppressor gene. Further studies of the mechanisms by which wild type and mutant p53 affect the growth of p53 negative FCLs may reveal important biochemical properties of p53 in relation to cell cycle control and differentiation of erythroid cells.
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PMID:Friend virus induced murine erythroleukaemia: the p53 locus. 163 45

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

We have used antisense oligonucleotides to study the roles of transforming growth factor beta (TGF-beta) and the two antioncogenes, retinoblastoma susceptibility (Rb) and p53, in the negative regulation of proliferation of early hematopoietic cells in culture. The antisense TGF-beta sequence significantly enhanced the frequency of colony formation by multi-lineage, early erythroid, and granulomonocytic progenitors, but did not affect colony formation by late progenitors. Single cell culture and limiting dilution analysis indicated that autocrine TGF-beta is produced by a subpopulation of early progenitors. Antisense Rb but not antisense p53 yielded similar results in releasing multipotential progenitors (colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) from quiescence. Rb antisense could partially reverse the inhibitory effect of exogenous TGF-beta. Anti-TGF-beta blocking antibodies, antisense TGF-beta, or Rb oligonucleotides all had similar effects. No additive effects were observed when these reagents were combined, suggesting a common pathway of action. Our results are consistent with the model that autocrine production of TGF-beta negatively regulates the cycling status of early hematopoietic progenitors through interaction with the Rb gene product.
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PMID:Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides. 171 34

Transfection of the wild-type p53 gene into malignant cell lines usually results in an inhibition of proliferation. However, the physiological function of the endogenous p53 gene product has been difficult to ascertain. In order to examine whether p53 is involved in the regulation of proliferation and/or differentiation of hematopoietic tissue, we modified a recently developed flow cytometric assay to assess p53 protein expression in normal human hematopoietic cells, primary leukemias, and selected leukemia cell lines. In normal human bone marrow, p53 protein was not detected in the proliferative, progenitor cell populations identified by the cell surface antigens CD34 (progenitor cells of multiple lineages) or glycophorin (erythroid precursors). In contrast, low but detectable levels of p53 protein were observed in the nonproliferative, mature lymphoid, granulocytic, and monocytic cell populations. Similarly, p53 levels increased and DNA synthesis decreased during 12-O-tetradecanoylphorbol-13-acetate-induced differentiation of ML-1 myeloblastic leukemia cells. Both of these results suggest that endogenous, wild-type p53 protein may play a role in hematopoietic cell maturation, possibly by contributing to the inhibition of proliferation that occurs during terminal differentiation. Leukemia cells deviated from this pattern of expression: (a) in contrast to the normal, proliferative bone marrow progenitor cells, a significant percentage of patient leukemia samples expressed detectable levels of p53 protein; and (b) leukemia cell lines exhibited lineage-specific abnormalities in p53 expression, with overexpression in lymphoid cell lines and lack of expression in myeloid cell lines.
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PMID:Levels of p53 protein increase with maturation in human hematopoietic cells. 186 48

The Friend helper leukemia virus (F-MuLV) induces in mice leukemias of the erythroid, lymphoid, and myeloblastic lineages. Erythroleukemic cell DNAs were examined for genetic alterations at loci described as common proviral integration regions in MuLV-induced myeloid or lymphoid leukemias or in Friend complex-induced erythroleukemias. No alteration of the Fim-1, Fim-2, Fim-3, pvt-1, and Spi-1 loci were detected in 17 erythroleukemias, p53 gene rearrangement was observed in 6 (30%) erythroleukemias and was always associated with a loss of the germ line allele. Interestingly, genetic alterations were also detected at two loci, c-myc and Pim-1, previously described as common provirus integration regions in T lymphoid leukemias. Rearrangements of these two genes were often associated with p53 gene alteration within the same tumor.
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PMID:Rearrangements of the Pim-1, c-myc, and p53 genes in Friend helper virus-induced mouse erythroleukemias. 214 96

A group of retroviruses carrying truncated viral genes has recently been suggested as the cause of new patterns of diseases. One such virus is the replication defective component of the Friend murine leukemia virus (F-MuLV) complex, called Friend spleen focus forming virus (F-SFFV). This virus induces erythroblastosis, and a virion envelope-related glycoprotein, gp55, encoded by F-SFFV has been suggested as the pathogenic gene. The role of the gp55 gene is, however, yet unclear in the apparently multistep erythroleukemogenesis. By separately producing transgenic mice harboring the whole F-SFFV DNA, the gp55 gene alone under the control of the retroviral long terminal repeat (LTR) and the gp55 gene under the control of cytoplasmic beta actin transcriptional regulatory unit, we show here that the gp55 gene is capable of inducing neoplastic proliferation of erythroid progenitor cells specifically in the absence of helper virus and other F-SFFV sequences. Under the control of the viral LTR the gp55 expression was detected only in leukemic tissues, but under the control of cytoplasmic beta-actin regulatory sequences, the gp55 was also expressed in a variety of normal tissues including preleukemic normal spleens. The development of erythroleukemia was suppressed under the genetic background of C57B1/6 mouse (resistant to F-MuLV; Fv-2rr), and required additional events even under the background of DDD mouse (susceptible to F-MuLV; Fv-2ss). The p53 and Spi-1 genes were frequently aberrant in transplanted tumors and cell lines derived from them, but were not in primary leukemic spleens.
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PMID:Env-derived gp55 gene of Friend spleen focus-forming virus specifically induces neoplastic proliferation of erythroid progenitor cells. 216 63

We report that highly purified human platelet factor 4 (PF4) inhibits human megakaryocytopoiesis in vitro. At greater than or equal to 25 micrograms/ml, PF4 inhibited megakaryocyte colony formation approximately 80% in unstimulated cultures, and approximately 58% in cultures containing recombinant human IL 3 and granulocyte-macrophage colony-stimulating factor. Because PF4 (25 micrograms/ml) had no effect on either myeloid or erythroid colony formation lineage specificity of this effect was suggested. A synthetic COOH-terminal PF4 peptide of 24, but not 13 residues, also inhibited megakaryocyte colony formation, whereas a synthetic 18-residue beta-thromboglobulin (beta-TG) peptide and native beta-TG had no such effect when assayed at similar concentrations. The mechanism of PF4-mediated inhibition was investigated. First, we enumerated total cell number, and examined cell maturation in control colonies (n = 200) and colonies (n = 100) that arose in PF4-containing cultures. Total cells per colony did not differ dramatically in the two groups (6.1 +/- 3.0 vs. 4.2 +/- 1.6, respectively), but the numbers of mature large cells per colony was significantly decreased in the presence of PF4 when compared with controls (1.6 +/- 1.5 vs. 3.9 +/- 2.3; P less than 0.001). Second, by using the human leukemia cell line HEL as a model for primitive megakaryocytic cells, we studied the effect of PF4 on cell doubling time, on the expression of both growth-regulated (H3, p53, c-myc,and c-myb), and non-growth-regulated (beta 2-microglobulin) genes. At high concentrations of native PF4 (50 micrograms/ml), no effect on cell doubling time, or H3 or p53 expression was discerned. In contrast, c-myc and c-myb were both upregulated. These results suggested the PF4 inhibited colony formation by impeding cell maturation, as opposed to cell proliferation, perhaps by inducing expression of c-myc and c-myb. The ability of PF4 to inhibit a normal cell maturation function was then tested. Megakaryocytes were incubated in synthetic PF4, or beta-TG peptides for 18 h and effect on Factor V steady-state mRNA levels was determined in 600 individual cells by in situ hybridization. beta-TG peptide had no effect on FV mRNA levels, whereas a approximately 60% decrease in expression of Factor V mRNA was found in megakaryocytes exposed to greater than or equal 100 ng/ml synthetic COOH-terminal PF4 peptide. Accordingly, PF4 modulates megakaryocyte maturation in vitro, and may function as a negative autocrine regulator of human megakaryocytopoiesis.
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PMID:Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide. 252 11

A comparative study on the expression of nuclear and cytoplasmic oncogenes was carried out using the Northern blotting technique, in Rauscher virus induced primary leukemias and the more malignant transformed cell lines derived from them. The latter grow permanently in vitro. Hyperplastic spleens obtained from mice recovering from anemia were analysed as controls. In addition to the detection of mRNAs, Southern blotting was carried out to observe whether rearrangement or amplification of oncogenes had occurred. The results show that the nuclear oncogenes c-myc, c-myb and p53 are strongly expressed in leukemic tissue, whereas c-fos transcripts show a much weaker hybridization. The expression of two of these oncogenes, c-myc and c-myb was followed during differentiation in myeloid leukemic cells and showed a gradual decrease when compared with the actin gene, which is constitutively transcribed. A large number of cytoplasmic oncogenes is expressed in the leukemic cells lines, i.e. c-abl, c-fms, c-fes, c-src, c-ros, c-H-ras, c-K-ras and N-ras. Of these, transcripts coding for c-abl and c-src were absent in blast cells of acute erythroid leukemias. Transcripts coding for c-erb, c-mos and c-sis could also not be detected. A number of putative oncogenes which are reported to play a role in Moloney and Friend virus induced leukemias for instance pim-1, fis-1, fim-1 and fim-2 were also used for screening. Only expression of pim-1 in Rauscher virus induced myeloid leukemic cells and in primary acute erythroid leukemias could be observed. At the DNA level no rearrangement or amplification of any of the oncogenes investigated could be detected. The results show that a number of oncogenes are expressed simultaneously in the same leukemic tissue or cell lines. It therefore seems likely that the presence of transcripts of different oncogenes is associated with the progression of leukemia, but is not the primary cause of leukemogenesis or of the transformation of these cells into established cell lines.
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PMID:Oncogene expression in Rauscher murine leukemia virus induced erythroid, myeloid and lymphoid cell lines. 291 75

The erythroleukemia induced by the Friend spleen focus-forming virus (SFFV) in mice exemplifies a multistep oncogenic process. Its sequential steps include a rapid polyclonal hyperplastic stage and a more slowly developing malignant stage characterized by autonomous erythroid cells. We report here that the helper virus normally present in mice infected by SFFV is not required for development of the second stage of transformation. In this study, mice were infected with a polycythemia-inducing variant of SFFV which was prepared as a helper-free stock (L. Wolff and S. Ruscetti, 1985, Science 228, 1549). Highly malignant cells could be detected in helper-free SFFV-infected mice by their transplantability into the omentum of sublethally irradiated mice, and erythroleukemia cell lines, typical of previously isolated Friend murine erythroleukemia cell lines, could be established from diseased spleens. Like their helper virus-containing counterparts, the lines established with helper-free SFFV are inducible for hemoglobin synthesis with a variety of chemicals, but not erythropoietin, and express p53, a marker of malignant transformation. Although the cells expressed SFFV encoded proteins, none expressed gene products of replication competent murine leukemia viruses.
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PMID:Induction of the autonomous stage of transformation in erythroid cells infected with SFFV: helper virus is not required. 301 73


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