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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 is overexpressed in many transformed cells and expression of the gene is known to alter during terminal differentiation of cells in culture. Through analysis of recombinant vectors expressing the chloramphenicol acetyl transferase (CAT) gene we found that two promoters map to the 5'-portion of the human p53 oncogene. One promoter, p53p1, maps upstream of the non-coding first exon and the second, p53p2, maps within the first intron. By primer extension analysis of cellular RNA from a number of human cell lines, we found that p53p2 is a functional promoter in vivo. In order to test whether differential regulation of these promoters may be correlated with the control of expression of the p53 gene during differentiation, we have measured the activity of the two promoters by their ability to direct expression of the CAT gene during terminal differentiation of the human promyelocytic leukemia cell line HL-60. HL-60 cells stably harboring Epstein-Barr virus-derived recombinant plasmids that express the CAT gene from either p53p1 or p53p2 were induced to undergo terminal differentiation by a variety of chemical inducers to either granulocytes or monocytes and expression of the CAT gene was measured. The results indicate that while expression of p53p1 remained constant, expression from p53p2 was induced 5- to 10-fold during differentiation of these cells to either granulocytes or monocytes. Similarly, the endogenous p53p2 was found to be induced in HL-60 cells undergoing differentiation. Although the product of the p53p2 initiated transcript has not yet been characterized these results indicate that altered regulation of these two promoters may be important in modulating the expression of mRNA from this gene during terminal differentiation.
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PMID:Two promoters that map to 5'-sequences of the human p53 gene are differentially regulated during terminal differentiation of human myeloid leukemic cells. 266 45

Southern blot analysis of various genes was used to compare the human promyelocytic leukemia cell line HL-60 and the BII cell line, which reportedly arose as a spontaneous differentiation inducer-resistant variant from an HL-60 culture. Granulocyte-macrophage colony stimulating factor gene restriction fragment polymorphism, due to a partial deletion of one of the alleles of this gene in HL-60, was not observed in the BII cells. Furthermore, the p53 oncogene, most of which is deleted in the HL-60 cell line, was found to be intact in the BII cell line. Human leukocyte antigen typing revealed that the two cell lines shared the A locus but differed at the B locus. Several unique restriction fragments hybridizing to human leukocyte antigen class I and DR beta gene probes were observed in the DNA digests of each cell line. Altogether these data provide definitive evidence that BII represents a human cell line of different origin than HL-60. Further lineage determination of this cell line could add a useful member to the group of leukemic cell lines.
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PMID:Southern blot analysis of BII cell line--a putative variant of HL-60. 288 53

We used somatic-cell hybrids, containing as their only human genetic contribution part or all of chromosome 17, as donors for chromosome-mediated gene transfer. A total of 54 independent transfectant clones were isolated and analyzed by use of probes or isoenzymes for greater than 20 loci located on chromosome 17. By combining the data from this chromosome-mediated gene transfer transfectant panel, conventional somatic-cell hybrids containing well-defined breaks on chromosome 17, and in situ hybridization, we propose the following order for these loci: pter-(TP53-RNP2-D17S1)-(MYH2-MYH1)-D17Z 1-CRYB1-(ERBA1-GCSF-NGL)-acute promyelocytic leukemia breakpoint-RNU2-HOX2-(NGFR-COLIAI-MPO)-GAA-UM PH-GHC-TK1-GALK-qter. Using chromosome-mediated gene transfer, we have also regionally localized the random probes D17S6 to D17S19 on chromosome 17.
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PMID:Construction of a genetic map of human chromosome 17 by use of chromosome-mediated gene transfer. 318 46

Analysis of fresh human tumors have indicated that patients with B type lymphoproliferative diseases and the majority of patients with acute lymphoblastic leukemia (ALL) express elevated levels of p53 production. It is suggested that in these human malignancies, p53 may provide a novel tool for monitoring cancer activity. Conversely, p53 is not expressed in acute myeloid leukemias, myeloproliferative diseases, or myeloid leukemic cell lines. Analysis of the p53 gene structure indicated the existence of similar patterns of p53 restriction fragments in producer and nonproducer cells, which suggests that the p53 gene is not altered in the latter. However, in one case of acute promyelocytic leukemia (APL), we have observed a rearrangement in the p53 gene. Karyotype analysis has indicated that these APL cells do not contain the typical 15;17 translocation. In other APL patients who exhibit a 15;17 translocation, we found no genomic changes of the p53, suggesting that the p53 gene, which was recently mapped to the short arm of chromosome 17 in the human, is not structurally related to the typical chromosomal break point found in the long arm of chromosome 17 of APL patients.
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PMID:Expression of p53 in human leukemia and lymphoma. 352 60

The p53 tumor suppressor gene is thought to be required for the induction of programmed cell death (apoptosis) initiated by DNA damage. We show here, however, that the human promyelocytic leukemia cell line HL-60, which is known to be deficient in p53 because of large deletions in the p53 gene, can be induced to undergo apoptosis following X-irradiation. We demonstrate that the decision to undergo apoptosis in this cell line appears to be made at a G2 checkpoint. In addition, we characterize an HL-60 variant, HCW-2, which is radioresistant. HCW-2 cells display DNA damage induction and repair capabilities identical to those of the parental HL-60 cell line. Thus, the difference between the two cell lines appears to be that X-irradiation induces apoptosis in HL-60, but not in HCW-2, cells. Paradoxically, HCW-2 cells display high levels of expression of bax, which enhances apoptosis, and no longer express bcl-2, which blocks apoptosis. HCW-2 cells' resistance to apoptosis may be due to the acquisition of expression of bcl-XL, a bcl-2-related inhibitor of apoptosis. In summary, apoptosis can be induced in X-irradiated HL-60 cells by a p53-independent mechanism at a G2 checkpoint, despite the presence of endogenous bcl-2. The resistance shown by HCW-2 cells suggests that bcl-XL can block this process.
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PMID:Evidence for a G2 checkpoint in p53-independent apoptosis induction by X-irradiation. 756 37

beta-Lapachone and certain of its derivatives directly bind and inhibit topoisomerase I (Topo I) DNA unwinding activity and form DNA-Topo I complexes, which are not resolvable by SDS-K+ assays. We show that beta-lapachone can induce apoptosis in certain cells, such as in human promyelocytic leukemia (HL-60) and human prostate cancer (DU-145, PC-3, and LNCaP) cells, as also described by Li et al. (Cancer Res., 55: 0000-0000, 1995). Characteristic 180-200-bp oligonucleosome DNA laddering and fragmented DNA-containing apoptotic cells via flow cytometry and morphological examinations were observed in 4 h in HL-60 cells after a 4-h, > or = 0.5 microM beta-lapachone exposure. HL-60 cells treated with camptothecin or topotecan resulted in greater apoptotic DNA laddering and apoptotic cell populations than comparable equitoxic concentrations of beta-lapachone, although beta-lapachone was a more effective Topo I inhibitor. beta-Lapachone treatment (4 h, 1-5 microM) resulted in a block at G0/G1, with decreases in S and G2/M phases and increases in apoptotic cell populations over time in HL-60 and three separate human prostate cancer (DU-145, PC-3, and LNCaP) cells. Similar treatments with topotecan or camptothecin (4 h, 1-5 microM) resulted in blockage of cells in S and apoptosis. Thus, beta-lapachone causes a block in G0/G1 of the cell cycle and induces apoptosis in cells before, or at early times during, DNA synthesis. These events are p53 independent, since PC-3 and HL-60 cells are null cells, LNCaP are wild-type, and DU-145 contain mutant p53, yet all undergo apoptosis after beta-lapachone treatment. Interestingly, beta-lapachone treatment of p53 wild type-containing prostate cancer cells (i.e., LNCaP) did not result in the induction of nuclear levels of p53 protein, as did camptothecin-treated cells. Like other Topo I inhibitors, beta-lapachone may induce apoptosis by locking Topo I onto DNA, blocking replication fork movement, and inducing apoptosis in a p53-independent fashion. beta-Lapachone and its derivatives, as well as other Topo I inhibitors, have potential clinical utility alone against human leukemia and prostate cancers.
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PMID:Beta-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response. 764 Nov 80

beta-Lapachone, a plant product, has been shown to be a novel inhibitor of DNA topoisomerase I, with a mode of action different from camptothecin and a chemical structure distinct from those of current anti-cancer drugs. We observed that beta-lapachone, at concentrations of less than 8 microM, induces cell death with characteristics of apoptosis in human prostate cancer cell lines. This effect of beta-lapachone was also observed in a human promyelocytic leukemia cell line (HL-60). beta-Lapachone-induced apoptosis is independent of p53 expression, and ectopic overexpression of bcl-2 did not confer significant resistance to beta-lapachone. Among other human carcinoma and adenoma cell lines tested, human breast and ovary carcinoma showed sensitivity to the cytotoxic effect of beta-lapachone without manifesting signs of apoptosis. These results suggest that beta-lapachone is a potential compound to be added to cancer chemotherapy, particularly for prostate cancer.
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PMID:Induction of apoptosis by beta-lapachone in human prostate cancer cells. 764 Nov 81

The product of the p53 tumor-suppressor gene has been shown to function in apoptosis and cell cycle regulation. However, there is little information regarding the regulation of apoptosis in cell differentiation. We investigated the relationship between p53-dependent apoptosis and differentiation induction using human promyelocytic leukemia HL-60 cells transfected with pMAMneo expression vectors containing dexamethasone-inducible wild-type p53 (wt-p53) cDNA inserts. Continuous exposure of the pMAMneo/wt-p53 transfectants to 1 microM dexamethasone for more than 24 h caused overexpression of wt-p53 followed by cell death with morphological changes typical of apoptosis. Using the wt-p53-inducible HL-60 cells, we examined the effects of differentiation inducers on the wt-p53-dependent apoptosis. All-trans retinoic acid (all-trans RA) at 1 nM or granulocyte macrophage colony-stimulating factor (GM-CSF) at 35 pM inhibited the wt-p53-induced apoptosis over a 42-h treatment. The apoptosis inhibition by GM-CSF, but not all-trans RA, was abolished by specific inhibitors of protein kinase C. These results suggest that extracellular signals involved in the differentiation induction could modulate the wt-p53-dependent apoptosis through protein kinase C-dependent and independent pathways.
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PMID:Inhibition by differentiation-inducing agents of wild-type p53-dependent apoptosis in HL-60 cells. 773 Jan 47

We have previously reported the absence of mutations within exons 5-9 of the p53 gene in a panel of 30 cases of acute promyelocytic leukemia (APL), which represent the M3 FAB type of acute myeloid leukemia (AML). In the present report, we extend our analysis of p53 gene mutations to 70 cases of AML representative of the other FAB types of the disease, including M1 (16 cases), M2 (20 cases), M4 (17 cases), M5 (12 cases), and M6 (5 cases). DNAs were analyzed for p53 gene mutations in exons 5 to 9 by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and direct sequencing of PCR-amplified products. Mutant p53 alleles were detected in 5 of 70 cases; 1 case in exon 5, 2 cases in exon 6, and 2 cases in exon 7. The alterations of the p53 gene were represented by point mutation leading to an amino acid substitution in four cases, and deletion in the remaining case. In four of the five cases, direct sequencing indicated the loss of the normal p53 allele; in the remaining case, two mutations were detected, presumably involving both p53 alleles. Three cases showed mutations at diagnosis; in the remaining two, the mutations were observed in clinical relapse but not at diagnosis. Our results confirm the relatively low incidence of p53 mutations in AML and further support the evidence that p53 plays a role in leukemogenesis through a recessive mechanism (two-hit model) of inactivation of tumor suppressor activity.
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PMID:Analysis of p53 gene mutations in acute myeloid leukemia. 803 81

Overexpression of wild-type p53 gene in malignant cell lines has been shown to inhibit cell proliferation in a number of cases. However, endogenous p53 protein seems to play little role in normal cell-cycle control as suggested by the normal development of p53 null mice, and by the low p53 protein levels expressed in most cell types. Recently, increased expression of endogenous p53 protein has been observed during the cellular response to DNA damage, as well as during differentiation of human hematopoietic cells. To study the role of the p53 gene in hematopoietic differentiation, we introduced the wild-type p53 gene or the temperature-sensitive p53(Val135) mutant into p53-deficient HL-60 promyelocytic leukemia cells. Morphological analysis, flow-cytometric determination of granulocytic or monocytic surface markers, and ability to reduce nitroblue tetrazolium (NBT) demonstrated that expression of exogenous wild-type p53 gene in HL-60 cells induces differentiation through the granulocytic pathway. Proliferation and cell-cycle analysis performed early after expression of wild-type p53 showed that induction of differentiation is not coupled with growth arrest, which suggests that p53 is involved in differentiation independently of its activity on the cell cycle.
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PMID:Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells. 816 88


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