Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells, and we thus analyzed its underlying mechanisms. Carcinoma cells constitutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFRbeta and gp130, respectively. Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF-7, ZR-75-1, Hs-700T and Panc-1) and suppressed cell growth in 3 lines (AZ-521, GBK-1 and HT-29). LIF significantly induced an immediate early response of genes c-fos and junB 3 hr after stimulation, but not of c-jun during the process of proliferation of MCF-7 and Hs-700T cells, with maximum levels at 30-60 min. The cell-cycle-related gene cyclin E was also induced in MCF-7 and Hs-700T cells, whereas cyclinA, cdk2, c-myc, c-myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ-521 and GBK-1 cells. LIF increased the number of TUNEL-positive cells in AZ-521 cells and DNA fragmentation in AZ-521 and GBK-1 cells. LIF induced apoptosis related genes c-myc and ICE during suppression of cell growth, but p53, p21, c-fos, cyclin A and cyclin E were not induced. Our results suggest that LIF is linked to cell proliferation and apoptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of oncogenes.
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PMID:Leukemia inhibitory factor induces apoptosis and proliferation of human carcinoma cells through different oncogene pathways. 925 11

Recently, Frey (Cytometry 17:310-318, 1994) demonstrated that TO-PRO-3 iodide (TP3) can be excited indirectly by a 488 nm laser line through energy transfer by propidium iodide (PI). In the present study, we investigated whether PI-TP3 energy transfer can help to overcome spectral cross talk problems associated with the combined use of fluorescein isothiocyanate (FITC), R-phycoerythrin (PE), and PI. Mixtures of keratin 8/18 FITC-labeled, keratin 8/18-PE-labeled, and unlabeled MCF-7 breast carcinoma cells were prepared and stained for DNA with PI (100 microM). The effect of adding a range of TP3 concentrations (0.001 to 16 microM) to these mixtures was evaluated. The combined use of PI and TP3 was further evaluated using mixtures of unlabeled and p53 FITC-labeled COV362.cl4 ovarian cancer cells and mixtures of unlabeled and p53 FITC-labeled COV362.cl4 cells and peripheral blood lymphocytes (PBL), additionally stained for keratin 8/18 (PE). Finally, a human ovarian ascites tumor specimen was triple-stained for keratin 8/18 (PE), vimentin (FITC) and DNA or keratin 8/18 (PE), PCNA (FITC) and DNA. Addition of TP3 allowed complete correction for spectral cross talk of PE/PI into the green fluorescence detector (FL1). Only minimal (FL1 - %FL2) compensation was required at a TP3 concentration of 2.0 microM in the presence of PI (100 microM). The PI spectral cross talk into the orange fluorescence detector (FL2) was reduced by about 50% using the same photomultiplier (PMT) settings. Although addition of TP3 reduced the signal-to-background ratio by about 30%, the advantage gained through full compensation for spectral cross talk resulted in an improved discrimination of p53-positive and -negative subpopulations in a mixture of human PBL and COV362.cl4 cells. Furthermore, vimentin-negative and PCNA-negative cells were better resolved in a human DNA-aneuploid ovarian ascites tumor after staining the DNA with PI/TP3, rather than with PI alone. We conclude that the addition of TP3 to PI improves the combined measurement by single-laser flow cytometry of DNA-ploidy and antigen expression in heterogenous clinical samples.
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PMID:Improved single laser measurement of two cellular antigens and DNA-ploidy by the combined use of propidium iodide and TO-PRO-3 iodide. 926 54

Incubation in vitro of recombinant wild-type murine p53 protein with S-nitroso-N-acetyl-DL-penicillamine [a nitric oxide (NO)-releasing compound] has resulted in a change of p53 conformation and also in a significant decrease of its specific DNA binding activity. Similarly, upon treatment with S-nitroso-N-acetyl-DL-penicillamine (2-5 mM) or S-nitroso-glutathione (1-2 mM), human breast cancer cells (MCF-7), which express wild-type p53, rapidly accumulated p53 protein in the nuclei. This p53 protein, however, possessed a significantly decreased activity of specific DNA binding. On the other hand, lower concentrations of NO donors (0.25-0.5 mM) stimulated p53 accumulation as well as its DNA binding activity. These results suggest that excess NO produced in inflamed tissues could play a role in carcinogenesis by impairing the tumor suppressor function of p53.
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PMID:Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. 926 97

7-Hydroxystaurosporine (UCN-01) is a selective protein kinase C inhibitor in clinical trial for cancer treatment. In this study, we found that nanomolar concentrations of camptothecin (CPT), a topoisomerase I inhibitor, arrest or delay cell cycle progression during the S and G2 phases in p53 mutant human colon carcinoma HT29 cells and that UCN-01 abrogates the S-phase arrest or delay induced by CPT. Under these conditions, CPT increased cyclin A levels and cyclin A/cyclin-dependent kinase 2 activity. UCN-01 prevented the increase of cyclin A/cyclin-dependent kinase 2 activity induced by CPT and enhanced Cdc2 kinase activity. Replication protein A (RPA2) was hyperphosphorylated after CPT treatment, and this effect was also abrogated by UCN-01. UCN-01 potentiated the cytotoxicity of CPT and reduced by 6-fold the concentration of CPT required to kill 50% of the HT-29 cells, as determined by clonogenic assays. This effect was observed at concentrations of UCN-01 that alone were not cytotoxic and had no detectable effect on cell cycle progression. UCN-01 markedly potentiated the cytotoxicity of CPT also in HCT116/E6 and MCF-7/ADR cells defective for p53 function, whereas significantly less potentiation was observed in p53-wild-type HCT116 and MCF-7 cells. These results suggest the existence of an S-phase checkpoint that delays replication and that may extend the time available for DNA repair. Thus, pharmacological abrogation of CPT-induced S- and G2-phase checkpoints by UCN-01 may provide an effective strategy for enhancing the chemotherapeutic activity of CPT, particularly against p53-defective tumors.
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PMID:Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53 function. 930 89

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D3, and tetradecanoylphorbol acetate (TPA) are potent negative growth regulators of breast cancer cells. In this study, we compared the mechanism of action of these two compounds in MCF-7 cells and a vitamin D3-resistant variant (MCF-7D3Res). In parental MCF-7 cells, 1,25-(OH)2D3 induced morphological and biochemical markers of apoptosis (chromatin and nuclear matrix condensation and DNA fragmentation), whereas TPA induced growth arrest without apoptosis. Both 1,25-(OH)2D3 and TPA independently up-regulated the vitamin D receptor, p21, and the hypophosphorylated form of retinoblastoma (Rb) protein. The growth regulatory effects of 1,25-(OH)2D3 and TPA did not correlate with induction of p53 protein expression. When both compounds were added simultaneously, synergistic effects on MCF-7 cell number were observed, and cell cycle regulatory proteins were down-regulated. The MCF-7D3Res cells, which are not sensitive to 1,25-(OH)2D3, were growth inhibited by TPA, and TPA partially sensitized MCF-7D3Res cells to the growth inhibitory effects of 1,25-(OH)2D3. In MCF-7D3Res cells, 1,25-(OH)2D3 treatment had minimal effects on p21 or Rb protein expression, whereas TPA down-regulated Rb protein and transiently up-regulated p21. These studies indicate dissociation between the pathways triggered by 1,25-(OH)2D3 and TPA, which mediate growth regulation in MCF-7 cells. Because both compounds induce growth arrest, but only 1,25-(OH)2D3 mediates apoptosis, we conclude that cell cycle arrest is not sufficient to trigger cell death of MCF-7 cells, and that 1,25-(OH)2D3 generates distinct signals which lead to induction of apoptosis in breast cancer cells.
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PMID:Differential effects of 1,25-dihydroxyvitamin D3 and tetradecanoylphorbol acetate on cell cycle and apoptosis of MCF-7 cells and a vitamin D3-resistant variant. 934 95

Thyroid hormone nuclear receptors (TRs) are ligand-dependent transcription factors which regulate growth, differentiation, and development. The molecular mechanisms by which TRs mediate these diverse effects are unclear. One emerging hypothesis suggests that TRs could mediate these diverse effects via cooperation with different transcription factors/receptors. Indeed, we have recently shown that the human TR subtype beta1 (h-TRbeta1) interacts with the tumor suppressor p53. p53 is a transcription factor that plays a critical role in cell cycle regulation and tumor development. To assess the physiological relevance of the interaction of h-TRbeta1 with p53, the present study addressed the question as to whether the functions of h-TRbeta1 could be modulated by p53. We first compared the h-TRbeta1-mediated transcriptional activity in two pairs of isogenic cell lines, RKO/RKO E6 and MCF-7/MCF-7 E6. RKO and MCF-7 cells are colon and breast carcinoma cell lines, respectively, that contain p53 but lack TRbeta1. The isogenic RKO E6 and MCF-7 E6 cells are stable clones expressing high levels of papillomavirus type 16 E6 protein. In these cells, the level of p53 protein was lower than the parental cells. The impairment of p53 functions in these E6-containing cells led to an activation of TRbeta1-mediated transcriptional activity. Furthermore, in a growth hormone-producing cell line in which the expression of the growth hormone gene is positively regulated by TRs, overexpression of the wild-type p53 led to repression in the expression of the growth hormone gene. Thus, TRs could cross-talk with p53 in its signaling pathways to regulate gene regulatory functions. The present findings further strengthen the hypothesis that mediation of the pleiotropic effects of T3 requires the cooperation of TRs with a large network of transcription factors.
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PMID:Tumor suppressor p53 is a negative regulator in thyroid hormone receptor signaling pathways. 936 Sep 71

The highly metastatic amelanotic C8161 human melanoma line was found to exhibit complete dominance of its undifferentiated and metastatic phenotype in multiple somatic cell hybridization studies designed to bypass the presence of potential tumor suppressor genes. In a three armed approach involving somatic cell fusions of C8161 with recipient lines of greater differentiation, different lineage, and different tumorigenicity status, the metastatic and undifferentiated phenotype of C8161 was promiscuously dominant. In somatic cell hybrids produced between the C8161 and a group of non-metastatic human melanoma lines which exhibited melanocyte differentiation markers including S100, HMB-45, NKI/C3, and melanin, the fusions were uniformly metastatic and undifferentiated. In somatic cell hybrids of C8161 and MCF-7 the fusions exhibited an estrogen independent and unresponsive, estrogen receptor (ER) negative, and highly metastatic phenotype. In fusions between C8161 and HMS-1, an immortalized 'benign' human myoepithelial line which produced an abundant extracellular matrix (ECM) and high levels of protease and angiogenic inhibitors including maspin, tissue inhibitor of metalloproteinase-1 (TIMP-1), alpha1-antitrypsin (alpha1-AT), protease nexin II (PN-II), thrombospondin-1 and soluble basic fibroblast growth factor (bFGF) receptors, the hybrids showed complete absence of matrix, absent maspin expression, markedly decreased protease inhibitor and angiogenic inhibitor production, high levels of proteases and angiogenic factors, and a highly metastatic phenotype. In our somatic cell fusions, the human-human hybrids represented true and complete fusions and not hybrid clones selected for by loss of dominant-acting growth suppressor genes. This finding was supported by detailed comparative genomic hybridization (CGH) studies, Q-banding karyotype analysis, and autofusions of representative clones. The purposeful creation of inherently unstable human-murine fusions between C8161 and B16-F1 where loss of putative suppressor loci would be expected, resulted in fusions exhibiting decreased growth and non-metastatic behavior with progressive chromosomal loss. Neither p53, nm23, DNA methyltransferase, activated ras, fibroblast growth factor-4 (FGF-4), or epidermal growth factor receptor (EGFR) mediated the acquisition of the metastatic or undifferentiated phenotype within the C8161-human fusions. These studies are the first studies ever to successfully transfer the complete metastatic phenotype by somatic cell fusion and support the presence of a new high level regulatory pathway(s) involving dominant trans-acting factors which act pleiotropically to regulate an undifferentiated and highly metastatic phenotype.
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PMID:Evidence of a dominant transcriptional pathway which regulates an undifferentiated and complete metastatic phenotype. 936 25

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 plays a major role in the induction of G1 cell cycle arrest following DNA damage and is known to be regulated by p53-dependent and -independent pathways. Here, we show that p21WAF1/CIP1 transcription is also regulated, independently of p53, by the cis elements that are located downstream of the transcription start site. A cDNA fragment of approximately 180 bp, located 260 bases 3' to the translation termination codon of p21WAF1/CIP1 cDNA, was cloned in both the sense and antisense orientations downstream of the CMV promoter, upstream of the SV40 promoter, and both upstream and downstream of the p21WAF1/CIP1 promoter in the plasmids carrying the luciferase reporter gene. The constructs were transiently transfected in human breast carcinoma cells MCF-7 and MDA-MB-468 and a Syrian hamster smooth muscle cell line DDT1MF2 and were found to elicit 2-3-fold or higher repression of luciferase activities. By using overlapping deletions of the above 180-bp fragment, we identified a 48-bp subfragment that contains putative cis element(s) that participate in the transcriptional repression of the p21WAF1/CIP1 gene. The overlapping subfragments bind, in vitro, to specific proteins present in the nuclear extracts of MDA-MB-468 and DDT1MF2 cells. We, therefore, propose that additional mechanism(s) exist that regulate expression of the cellular p21WAF1/CIP1 and may contribute to p21WAF1/CIP1-dependent control of the cell cycle.
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PMID:Transcriptional repression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 gene mediated by cis elements present in the 3'-untranslated region. 937 14

Fas is a cell-surface protein which belongs to the tumor-necrosis-factor-receptor family. Signals through Fas are able to induce apoptosis in sensitive cells, and thus modalities for regulating the level of Fas expression on tumor cells are needed. We have studied cellular responses to gamma irradiation. The level of p53 tumor-suppressor protein was found to be elevated 3 hr after irradiation of p53wild-type MCF-7 breast-carcinoma cells. Interestingly, accumulation of p53 was followed by up-regulation of surface Fas levels between 4 and 8 hr after irradiation. The level of Fas up-regulation was dependent on dose and, whereas elevation in the level of p53 was transient, enhancement of Fas expression was stable. Fas up-regulation occurred coincidentally with induction of G1 cell-cycle arrest, a post-irradiation phenomenon known to be dependent on wild-type-p53 activity. We studied 9 other tumor lines, 2 with wild-type p53, 5 with mutant p53, and 2 expressing no p53. All lines expressing wild-type p53 were found to arrest in G1 and to up-regulate Fas after irradiation. In contrast, all 7 p53null and p53mutant lines failed not only to arrest their cell cycles in G1 phase, but also to up-regulate Fas levels in response to treatment. These findings demonstrate a direct correlation between wild-type-p53 activity and Fas up-regulation after treatment with ionizing radiation, strongly suggesting that post-irradiation Fas up-regulation is dependent on wild-type-p53 activity. Since low doses of radiation were sufficient to modulate Fas expression, up-regulation of the Fas death receptor may have clinical implications following radiotherapy.
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PMID:Up-regulation of Fas (CD95) in human p53wild-type cancer cells treated with ionizing radiation. 939 58

The cytotoxicity of a recombinant adenovirus expressing the wild type tumor suppressor gene p53 (AdWTp53) was studied in two human breast cancer MCF-7 sublines selected for resistance to adriamycin (MCF-Adr) and mitoxantrone (MCF-Mito). Although the levels of wild type p53 protein following infection with AdWTp53 are comparable in all cell lines, the two drug-resistant MCF-7 sublines were 300- and 18-fold more sensitive to killing by AdWTp53 compared with the drug-sensitive parental MCF-7 cell lines. In each cell line, AdWTp53 infection led to cell cycle arrest, and reduction of Cdk2 and cyclin B1-Cdc2 activity. Nucleosomal DNA fragmentation analysis (as a function of apoptosis) following AdWTp53 infection revealed that, while the parental MCF-7 cells failed to undergo apoptosis, both drug-resistant cell lines showed distinct DNA laddering. In MCF-Adr cells, a combination treatment of AdWTp53 and adriamycin was much more toxic than either of the reagents used individually. Finally, exposure of a mixed population of MCF-Adr and CD34+ cells to AdWTp53 selectively prevented MCF-Adr cell colony formation, while there was no inhibition of CFU-GM colony formation from CD34+ cells. These findings suggest that some drug-resistant human breast cancers may be effectively treated with adenovirus expressing wild type p53.
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PMID:A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers. 940 9


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