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)

Pluripotent hematopoietic stem cells (PHSCs) show self-renewal and give rise to all blood cell types. The extremely low number of these cells in primary hematopoietic organs and the lack of culture systems that support proliferation of undifferentiated PHSCs have precluded the study of both the biology of these cells and their clinical application. We describe here cell lines and clones derived from PHSCs that were established from hematopoietic cells from the fetal liver or bone marrow of normal and p53-deficient mice with a combination of four growth factors. Most cell lines were Sca-1+, c-Kit+, PgP-1+, HSA+, and Lin- (B-220-, Joro 75-, 8C5-, F4/80-, CD4-, CD8-, CD3-, IgM-, and TER 119-negative) and expressed three new surface markers: Joro 177, Joro 184, and Joro 96. They did not synthesize RNA transcripts for several genes expressed at early stages of lymphocyte and myeloid/erythroid cell development. The clones were able to generate lymphoid, myeloid, and erythroid hematopoietic cells and to reconstitute the hematopoietic system of irradiated mice for a long time. The availability of lymphohematopoietic stem cell lines should facilitate the analysis of the molecular mechanisms that control self-renewal and differentiation and the development of efficient protocols for somatic gene therapy.
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PMID:Long-term culture of lymphohematopoietic stem cells. 864 61

Recent evidence has shown that p53 overexpression in leukemic cells may be a consequence of p53 gene mutation or can occur via posttranslational modification mechanisms. While mutant forms of p53 may stimulate cell proliferation and transformation, wild-type p53 may inhibit DNA synthesis and cause leukemic cells to enter apoptosis. Nine bone marrow biopsies of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with known p53 overexpression were analyzed for evidence of apoptosis of both leukemic blasts and of background hematopoietic cells. This was quantified and compared with that seen in p53- AML and MDS and in normal control marrows. The rate of cell death due to apoptosis was measured by in situ end-labeling of fragmented DNA with the following results: mean values of apoptotic cells/mm2 of BM, p53+ AML and MDS (9 cases), 2.41 +/- 1.7; p53- AML and MDS (10 cases), 0.16 +/- 0.1; control marrows (20 samples), 0.05 +/- 0.0. Our results showed a significant association (P < 0.001) between p53 overexpression and increased apoptosis in all cases studied. The difference was entirely caused by the high rate of cell death observed in the erythroid and myeloid precursor cells of these marrows. These findings suggest that p53+ AML and MDS are a distinct group of marrow disorders characterized by a high rate of intramedullary cell death. This may explain why patients with p53+ leukemic disorders show excessive marrow sensitivity to chemotherapy with prolonged marrow suppression associated with the presence of cytogenetically abnormal blasts that display great drug resistance.
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PMID:p53 overexpression in myeloid leukemic disorders is associated with increased apoptosis of hematopoietic marrow cells and ineffective hematopoiesis. 882 56

Retroviral insertional activation of the Fli-1 proto-oncogene is the first genetic event associated with the induction of erythroleukemias by the Friend murine leukemia virus (F-MuLV). Mutations within p53, which are only detected in cell lines established from transplanted tumors, have been previously shown to be associated with the immortalization of erythroleukemic cells in culture. In this study, we have demonstrated that primary erythroleukemic cells grown in liquid culture undergo rapid apoptosis independent of the stabilization of wild-type p53 protein. Further confirmation that the programmed cell death observed for liquid-cultured F-MuLV-induced primary erythroleukemic cells is largely p53 independent was provided by experimentation with a transgenic mouse line containing multiple copies of the dominant negative mutant p53Pro-193 allele. Erythroleukemic cells taken from tumor-bearing transgenic mice expressing high levels of the mutant p53Pro-193 undergo programmed cell death in culture in a manner that is largely identical to that observed for tumor cells derived from nontransgenic littermates. Furthermore, the rate of development of F-MuLV-induced erythroleukemias for both p53Pro-193-transgenic and nontransgenic littermates are similar. Moreover, cytogenetic analysis indicates that primary erythroleukemia cells are diploid, whereas chromosomal aberrations were observed in all established cell lines. These results are consistent with the notion that mutations within the p53 tumor suppressor gene affect genomic stability, subsequently leading to changes in gene expression that are associated with the immortalization of erythroid progenitor cells.
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PMID:p53-independent tumor growth and in vitro cell survival for F-MuLV-induced erythroleukemias. 895 33

Transforming growth factor-beta (TGF-beta) has been found to block the progression of the cell-cycle by up-regulating a Cdk inhibitor, p15, only in epithelial cells; on the other hand, wild-type p53 was shown to activate transcriptionally the gene for another Cdk inhibitor, p21. The regulatory effects of TGF-beta on hematopoietic tissues is poorly understood. Hence, we investigated the effect of TGF-beta on hematopoietic progenitor cells in p53-deficient mice to determine whether an inhibitory signal from TGF-beta is linked to p53 in hematopoietic regulation. We found that the proliferation of megakaryocyte-progenitors (CFU-Mk) in our wild-type mice was markedly inhibited by TGF-beta. Contrary to an earlier report, an erythroid and a granulocyte-macrophage progenitor, stimulated by IL-3, were not significantly inhibited, whereas TGF-beta also completely inhibited the growth of high-proliferative potential progenitor cells (HPP-CFC) in the marrow of mice with 5-fluorouracil (5FU), as reported. It is interesting that in the p53-deficient mice, the inhibitory action of TGF-beta on the HPP-CFC was incompletely abolished. The response curve we obtained for graded doses of TGF-beta suggests that there is, at least, a subpopulation of HPP-CFC which is less sensitive to the regulation by TGF-beta. In contrast to HPP-CFC, the CFU-Mk, which TGF-beta inhibited only in wild-type mice not treated with 5FU, remained inhibited in the p53-deficient strain. Thus, HPP-CFC might be regulated by TGF-beta through their signal pathways which are linked to p53.
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PMID:A fraction unresponsive to growth inhibition by TGF-beta among the high-proliferative potential progenitor cells in bone marrow of p53-deficient mice. 900 87

Camptothecin, an antitumor drug that specifically targets topoisomerase I, induced IW32 erythroleukemia cells to differentiate along the erythroid pathway, as demonstrated by the increased mRNA and protein expression of hemoglobin. Unlike other chemically induced erythroleukemia cell differentiation, no c-myc mRNA down-regulation was observed in the early phases of drug treatment. Among the heme-synthesizing enzyme mRNAs that were analyzed, only that of the erythroid-specific delta-aminolevulinic acid synthase (ALAS-E) was stimulated. Vanadate or benzylphosphonic acid, which inhibited protein tyrosine phosphatases (PTPase), blocked the camptothecin-induced differentiation. Maximal inhibition was attained if vanadate was added within the first 6 hr of camptothecin treatment, after which vanadate gradually lost its effectiveness. Camptothecin-induced expression of beta-globin or ALAS-E transcript levels was inhibited in the presence of cycloheximide or vanadate. It was also shown that vanadate blocked differentiation of IW32 cells induced by sodium butyrate, VM-26, and p53. Increased PTPase activity could be observed 48 hr after cells were treated with camptothecin, VM-26, or sodium butyrate. Analysis of PTPase activity in the course of camptothecin treatment showed elevated levels of PTPase in the cytosol and the nucleus, with a greater increase demonstrated in the cytosol than in the nucleus. Our results suggest that by stimulating the beta-globin and ALAS-E gene expression, PTPase plays a critical role in the induced differentiation of IW32 erythroleukemia cells.
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PMID:Protein tyrosine phosphatase-dependent activation of beta-globin and delta-aminolevulinic acid synthase genes in the camptothecin-induced IW32 erythroleukemia cell differentiation. 910 19

The zinc-finger transcription factor GATA-2 plays a critical role in maintaining the pool of early hematopoietic cells. To define its specific functions in the proliferation, survival, and differentiation of hematopoietic cells, we analyzed the hematopoietic potential of GATA-2-/- cells in in vitro culture systems for proliferation and maintenance of uncommitted progenitors or differentiation of specific lineages. From a two-step in vitro differentiation assay of embryonic stem cells and in vitro culture of yolk sac cells, we demonstrate that GATA-2 is required for the expansion of multipotential hematopoietic progenitors and the formation of mast cells, but dispensable for the terminal differentiation of erythroid cells and macrophages. The rare GATA-2-/- multipotential progenitors that survive proliferate poorly and generate small colonies with extensive cell death, implying that GATA-2 may play a role in both the proliferation and survival of early hematopoietic cells. To explore possible mechanisms resulting in the hematopoietic defects of GATA-2-/- cells, we interbred mutant mouse strains to assess the effects of p53 loss on the behavior of GATA-2-/- hematopoietic cells. Analysis of GATA-2-/-/p53-/- compound-mutant embryos shows that the absence of p53 partially restores the number of total GATA-2-/- hematopoietic cells, and therefore suggests a potential link between GATA-2 and p53 pathways.
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PMID:Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. 916 Jun 68

Mutations of the p53 tumor suppressor are often observed in various human malignancies including blast crisis of chronic myelogenous leukaemia (CML). The pattern of p53 mutation in CML shows some peculiarities as compared with the majority of other neoplasias. In particular, the substitutions at codon 273, one of the most common p53 alteration in various tumors, are not characteristic of CML. To test whether distinction in the pattern of p53 mutation are associated with certain peculiarities of biological effects of different mutant proteins in myeloid cells, we obtained and analysed a panel of human K562 cell sublines expressing various exogenous p53: human Pro156, His175, His194, Trp248 and His 273, or murine temperature-sensitive (ts) Val135 that has properties of mutant protein at 37 degrees C, but shows activities of wild-type (wt) p53 at 32 degrees C. We have found that expression of wt-p53 enhanced the dependence of cells on growth/survival factors, incubation of sparse (< 10(5) cells per/ml) K562/Val135 cultures at 32 degrees C caused apoptosis. In media conditioned by cells of different origin (K562, colorectal carcinoma LIM 1215, Rat1 fibroblast) the p53-dependent apoptosis was inhibited. In conditions that do not lead to apoptosis, the expression of ts-wt-p53 was accompanied by dramatic increase in the number of cells containing glycophorin A (GlycPhA) and "antigen of erythroblasts"--specific markers of erythroid differentiation. Unlike the wt-p53, the majority of tumor-derived mutant p53 (Pro156, His175, His194, Trp248) increased cells survival in media with low serum content and decreased the number of cell expressing GlycPhA, CD9, CD15 and CD71 differentiation antigens. On the other hand, expression of His273-p53 caused a significant augmentation in the number of CD9-positive cells and enhanced the dependence on growth/survival factors that are present in serum or conditioned media. The data obtained are consistent with the idea that unusual pattern of p53 mutations in CML can reflect the peculiarities of the effects of some mutant proteins on differentiation and/or viability of leukemic cells.
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PMID:[The effect of the tumor suppressor p53 and its mutant forms on the differentiation and viability of K562 leukemic cells]. 916 3

Mutations of the p53 tumor suppressor are often observed in various human tumors, including blast crisis of chronic myelogenous leukemia (CML). The pattern of p53 mutations in CML shows some peculiarities compared with majority of other malignancies. In particular, the substitutions at codon 273, one of the most common p53 alterations in various tumors, are not characteristic of CML. To test whether the distinctions in the pattern of p53 mutations are connected with some peculiarities of the biological effects of different mutant proteins in leukemic cells, we obtained and analyzed a panel of human K562 cell sublines expressing various exogenous p53; human Pro156, His175, His194, Trp248, and His273, or murine temperature-sensitive (ts) Val135 that has properties of mutant protein at 37 degrees C, but shows activities of the wild-type (wt) p53 at 32 degrees C. We have found that expression of wt-p53 enhanced the dependence of cells on growth/survival factors. Incubation of sparse (< 10(5) cells per/ml) K562/Val135 cultures at 32 degrees C caused apoptosis. In media conditioned by cells of different origin (K562, colorectal carcinoma LIM1215, Rat1 fibroblasts) the p53-dependent apoptosis was inhibited. Under such conditions the expression of ts-wt-p53 was accompanied by dramatic increase in the number of cells producing specific markers of erythroid differentiation-GlycPhA and Ag-Eb. Unlike to the wt-p53, the majority of tumor-derived mutant p53 (Pro156, His175, His194) increased cell survival in low serum and decreased the number of cells expressing Glyc-PhA, CD9, CD15, and CD71 differentiation antigens. On the other hand, expression of His273-p53 caused significant augmentation in the number of CD9-positive cells and enhanced the dependence on growth/survival factors that are present in serum or conditioned media. The data obtained allow to suggest that an unusual pattern of p53 mutations in CML reflects some peculiarities of biological effects of certain mutant proteins on differentiation and viability of leukemic cells.
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PMID:Distinct effects of various p53 mutants on differentiation and viability of human K562 leukemia cells. 926 86

A longitudinal investigation using fluorescence in situ hybridization (FISH) analysis, PCR-SSCP, and in situ detection of apoptosis by the terminal deoxynucleotidyl Transferase (TdT) method was carried out on 13 chronic myelogenous leukemia (CML) patients to study the p53 gene behavior and the apoptotic process during the course of the disease. At diagnosis, FISH showed no loss of the p53 gene on interphase nuclei, and no point mutation was detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. During the disease course, FISH analysis showed a significative loss of allele (LOA) rate for the p53 gene in eight patients that in seven cases was associated with a suppression of apoptotic process and the progressive expansion of the p53+/p53- clone. DNA sequencing showed in two of these eight patients a point mutation on the other allele, consisting in the formation of a stop codon in one case, and in a frameshift mutation in the other. Six patients had a myeloid blastic crisis (BC), five a lymphoid BC, and the other two an erythroid and an undifferentiated BC, respectively. All patients with myeloid BC and the one with undifferentiated BC disclosed a progressive expansion of the clone with p53 loss that was associated with a significant reduction in apoptosis. On the contrary in the 5 patients with lymphoid BC no significant p53 LOA rate was observed during the course of the disease. In these patients apoptotic process also persisted in the acute phase although in a lower rate as compared to CP.
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PMID:p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis. 930 15

Effective ex vivo purging techniques can decrease the likelihood of infusing bone marrow contaminated with leukemic cells during autologous transplantation. In preliminary studies, OL(1)p53, a 20-mer phosphorothioate oligonucleotide directed against p53 mRNA, decreased the number of acute myelogenous leukemia (AML) cells in vitro, suggesting a possible role for OL(1)p53 in purging bone marrow harvests of leukemia cells. To demonstrate that OL(1)p53 was nontoxic to hematopoietic progenitor cells, normal bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h, and hematopoietic progenitor cell survival was determined by in vitro colony assays. OL(1)p53 had no toxic effect on the growth of either myeloid (CFU-GM) or erythroid (BFU-E) progenitor cells. OL(1)p53 was then used to ex vivo purge bone marrow harvests from nine patients with either AML or myelodysplastic syndrome (MDS). Bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h before transplantation. The median times posttransplantation for the patient to recover an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet transfusion independence were 30 days and 56 days, respectively. Incubation of bone marrow cells with OL(1)p53 had no detrimental effect on the growth of hematopoietic progenitor cells, and transplantation of autologous bone marrow cells treated with the phosphorothioate oligonucleotide, OL(1)p53, resulted in successful recovery of circulating neutrophils following high-dose therapy in patients with AML or MDS. The data show that OL(1)p53 can be used safely to purge autologous bone marrow harvests from patients with leukemia.
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PMID:Ex vivo treatment of bone marrow with phosphorothioate oligonucleotide OL(1)p53 for autologous transplantation in acute myelogenous leukemia and myelodysplastic syndrome. 936 80

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