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)

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

The hemopoietic growth factor interleukin 3 (IL-3) supports the survival and proliferation of multipotent and committed progenitor cells in vitro. To elucidate the molecular mechanisms triggered by IL-3 we studied the expression of cell cycle-related genes in a recently established human IL-3-dependent clone (M-07e). No changes in the level of expression of early (c-myc), mid (ornithine decarboxylase), or mid-late G1 (p53, c-myb) cell cycle genes were detected after restoration of IL-3 in deprived cells. The fact that only late G1-S-phase genes [proliferating cell nuclear antigen (PCNA) thymidine kinase (TK), histone H3] are modulated by IL-3 suggests that this factor may control human cell proliferation by acting at the G1-S boundary.
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PMID:Interleukin 3-dependent proliferation of the human Mo-7e cell line is supported by discrete activation of late G1 genes. 199 64

Despite the profound differences between the chronic and blastic phases of chronic myelogenous leukaemia, no differences between chronic and blastic phase cells have been described at the molecular level. Differences have been found in the levels of expression of c-myc, c-myb and p53, which fell when chronic phase cells were cultured, while the levels of expression of the genes were stable when blastic crisis cells were cultured. In contrast c-fms expression increased and MRS expression decreased after culture of chronic or blastic phase cells. The data suggest that the regulation of expression of some genes in blastic crisis cells is unaltered while that of others is disrupted. It is not known whether the failure of c-myc, c-myb and p53 expression to fall during the culture of blastic phase cells is the cause of or a reflection of the failure of these cells to differentiate.
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PMID:Proto-oncogene expression in differentiating and non-differentiating chronic myelogenous leukaemia cells. 214 56

The development of human lung cancer may require multiple genetic deletions affecting a number of chromosomes, e.g., 1, 3, 11, 13, and 17. These genetic aberrations may induce the activation of proto-oncogenes (c-jun, ras, c-raf1) and the loss of tumor suppressor genes (p53). Some of the activated proto-oncogenes and tumor suppressor genes are more selectively expressed or absent in small-cell lung cancer (L-myc, c-myb, c-scr, Rb gene) or non-small-cell lung cancer (c-erbB-2, c-sis, c-fes). These genes may thus be of importance for selection of differentiation pathway. The c-myc oncogene is frequently amplified in small-cell lung cancer cell lines in a much higher frequency than in vivo. This indicates that c-myc seems to be related to tumor progression and a relatively late event in the lung cancer development. The uncontrolled production of multiple growth factors has been identified in human lung cancer cell lines. These factors can promote and inhibit the proliferation via paracrine and autocrine loops via specific receptors. The products from some of the activated proto-oncogenes (c-sis, c-erbB-2) are sequences homologous to a certain growth factor (PDGF) and a receptor (EGF) identified in lung cancer. The production and action of these growth factors may be of major importance for further activation of proto-oncogenes via intracellular signal transduction and specific oncogenic activation leading to further tumor progression.
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PMID:Gene amplification in human lung cancer. The myc family genes and other proto-oncogenes and growth factor genes. 217 59

The proto-oncogenes myc, myb, and p53 produce nuclear proteins which have been implicated in the regulation of proliferation or differentiation in a number of systems. The expression of these proto-oncogenes was studied in murine erythroleukemia (MEL) cells during (i) normal replication, (ii) DMSO-induced differentiation and (iii), alpha-difluoromethylornithine (DFMO)-restricted cell division and differentiation. The RNA levels of c-myc, c-myb, and p53 were all elevated during normal cellular proliferation; only c-myc expression declined when the cells stopped dividing although the rate of transcription for the gene was unaltered. In contrast, treatment of the cells with DFMO resulted in gradual cessation of cell replication and a decrease in transcription of c-myc, c-myb and p53. When the MEL cells were induced to differentiate with dimethyl sulfoxide (DMSO), a transient reduction in c-myc and c-myb RNA levels occurred immediately prior to the G1 arrest with a concomitant decrease in transcriptional activity, while p53 mRNA production was elevated without an increase in transcription. Similar changes of the proto-oncogene levels were observed when the MEL cells were incubated with DFMO and then later induced with DMSO, a protocol which restricts differentiation of the MEL cells. From these experiments we conclude that (i) c-myc, c-myb, and p53 are regulated independently at both the transcriptional and post-transcriptional levels, (ii) DFMO inhibits MEL cell proliferation and expression of several genes, including c-myc, c-myb and p53, and (iii) DFMO suppresses terminal differentiation but is unable to alter proto-oncogene changes associated with the early stages of differentiation.
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PMID:Transcriptional and post-transcriptional regulation of c-myc, c-myb, and p53 during proliferation and differentiation of murine erythroleukemia cells treated with DFMO and DMSO. 245 48

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

Protein import into the cell nucleus requires specific binding of nuclear proteins to the nuclear pore complex. Based on amino acid sequence "motifs" of known nuclear targeting signals, we identified peptides within a number of nuclear proteins with likely nuclear targeting potential and tested their function by transfecting into cells fusion genes that produce the cytoplasmic "reporter" protein, pyruvate kinase (PK), joined to the test sequence. Sequences within c-myb (PLLKKIKQ), N-myc (PPQKKIKS), p53 (PQPKKKP), and c-erb-A (SKRVAKRKL) oncoproteins that direct PK hybrids into the nucleus were identified. A peptide (GRKKRRQRRRAP) of the human immunodeficiency virus (HIV) tat protein (Tat), which contains two short basic regions, targets fusion proteins to the nucleolus. The COOH-terminal basic Tat region (QRRRAP) does not target PK hybrid proteins into the nucleus, but mutation of two basic amino acids in this region decreases but does not abolish nucleolar accumulation mediated by the entire Tat nucleolar targeting sequence. Moreover, the c-Myc nuclear targeting sequence fused to the COOH-terminal basic Tat region (PAAKRVKLDQRRRAP) effectively localizes PK hybrids to the nucleus and nucleolus. A similar sequence (FKRKHKKDISQNKRAVRR) in the human heat-shock protein HSP70 also localizes PK to the nucleus and nucleolus.
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PMID:Nuclear and nucleolar targeting sequences of c-erb-A, c-myb, N-myc, p53, HSP70, and HIV tat proteins. 255 99

Hexamethylene bisacetamide (HMBA) is a most effective compound as an inducer of MELC differentiation. HMBA-mediated terminal differentiation of MELC is a multistep process. There is a latent period during which a number of changes occur including the appearance of Ca2+ and phospholipid independent PKC activity in the cytosol, and modulation in expression of several genes, including c-myc, c-myb, c-fos and the p53 genes. During this latent period there is neither detectable commitment to terminal differentiation (including terminal cell division) or increased transcription of the globin genes. HMBA-mediated commitment to terminal differentiation is first detected at about 12 hr and increases in a stochastic fashion, until over 95% of the population has been recruited to terminal differentiation by 48 to 60 hr. Commitment is associated with persistent HMBA-mediated suppression of c-myb gene expression. By 36 to 48 hr, transcription of the globin genes has increased by 10 to 30 fold, whereas transcription of rRNA genes is suppressed. The steroid, dexamethasone, and the tumor promotor, phorbol-12-myristate-13-acetate, suppress HMBA-induced MEL cell terminal differentiation. The evidence indicates that these agents act at a late step during the latent period. Recently, we showed that MELC variants selected for resistance to vincristine have a marked increased sensitivity to HMBA. Compared to the parental MELC strains, vincristine resistant MELC are: A) responsive to 1/5 to 1/10 the concentration of HMBA; B) induced to terminal differentiation without a latent period and C) resistant to inhibition of HMBA induced terminal differentiation by dexamethasone or tumor promotor. The vincristine resistant MELC have characteristics of the multidrug resistant phenotype. A number of independently derived vincristine resistant MELC lines show similar altered response to HMBA. These findings suggest that vincristine resistance leads to a constitutive expression of a factor or factors induced by HMBA in vincristine sensitive (wild type) MELC during the latent period and which are essential to the transition to terminal differentiation.
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PMID:Induced differentiation of murine erythroleukemia cells (MELC) by polar compounds: marked increased sensitivity of vincristine resistant MELC. 261 74

We have devised an in vitro RNA elongation assay (nuclear "run-on" transcription) that is suitable for use with small amounts of primary embryonic tissue. The assay is sensitive enough to detect transcription of single-copy genes in 8 X 10(5) nuclei isolated from embryonic chicken lens epithelia, and gives no detectable hybridization to unrelated DNAs, such as phi X or pBR322. We have used this assay to examine transcription of delta-crystallin and six proto-oncogenes in lens epithelia of 6-day-old embryonic chickens. The results indicate that delta-crystallin, c-myc, p53, and c-fos are actively transcribed in these cells, while c-myb, N-ras, and c-mil are not transcribed at detectable levels.
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PMID:Nuclear run-on transcription from primary embryonic lens tissue. 264 83

The induction of murine erythroleukemia cells (MELC) to terminal differentiation by hexamethylene bisacetamide (HMBA) is accompanied by changes in the levels of c-myb and c-myc mRNA, and in p53 protein levels. We simultaneously examined the effects of HMBA on modulation of c-myb, c-myc and p53 mRNA and protein levels, and examined the relationship between these changes and commitment to terminal cell division. In MELC cultured with HMBA, c-myb protein levels paralleled c-myb mRNA levels except at 24h, when the protein level was equivalent to the level in control cultures, whereas the mRNA had decreased. The c-myc protein paralleled c-myc mRNA throughout induction. The p53 mRNA and protein behaved in a discordant fashion. The p53 protein decreased to very low levels between 4 and 8 h and remained low, while the mRNA, which initially decreased, reaccumulated by 24 and 48 h. Transfer of MELC after 12 to 48 h of culture with HMBA to medium without inducer resulted in rapid (less than 3 h) reaccumulation of the c-myb mRNA, c-myb protein, and p53 protein, and cessation of recruitment of cells to commitment. Cells already induced to commit to terminal differentiation continued to express the differentiated phenotype.
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PMID:Modulation of the c-myb, c-myc and p53 mRNA and protein levels during induced murine erythroleukemia cell differentiation. 264 54


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