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)

We have previously shown that forskolin and 3-isobutyl-1-methylxanthine (IBMX) increased accumulation of cisplatin (DDP) in DDP-sensitive 2008 human ovarian carcinoma cells in proportion to their ability to increase cAMP. Since the major function of cAMP is to activate protein kinase A, it was conjectured that the stimulation of DDP accumulation was mediated by a protein kinase A substrate. We now show that exposure of 2008 cells to forskolin resulted in phosphorylation of a prominent 52-kD membrane protein. Microsequencing of the band demonstrated it to be human beta-tubulin. Similarly, pretreatment of 2008 cells with the microtubule stabilizing drug taxol increased platinum accumulation in a dose-dependent manner. In 11-fold DDP-resistant 2008/C13*5.25 cells, decreased DDP accumulation was associated with enhanced spontaneous formation of microtubule bundles and decreased expression of beta-tubulin and the tubulin-associated p53 antioncogene relative to 2008 cells. 2008/C13*5.25 cells had altered sensitivity to tubulin-binding drugs, being hypersensitive to taxol and cross-resistant to colchicine. We conclude that pharmacologic alterations of tubulin enhance accumulation of DDP, and that the DDP-resistant phenotype in 2008/C13*5.25 cells is associated with tubulin abnormalities.
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PMID:In vitro modulation of cisplatin accumulation in human ovarian carcinoma cells by pharmacologic alteration of microtubules. 810 Aug 37

Our previous data have shown that isolated leukemic cells from progressive chronic lymphocytic leukemia (B-CLL) patients respond to growth stimulation in vitro and express high levels of p53, immunoreactive with the configuration-specific antibody PAb 240. We have now analyzed the in vitro survival of B-CLL cells in relation to Bcl-2, Bax alpha and p53 expression and compared this with the clinical progression of the disease. Leukemic cells from patients with progressive disease demonstrated higher in vitro survival, compared with non-progressive B-CLL and normal B cells. All cells were sensitive to treatment with a combination of glucocorticoid and cAMP. Bcl-2 protein levels were not related to clinical progression, as measured by flow cytometry. Competitive PCR showed that Bcl-2 mRNA was over-expressed in most of the B-CLL samples and that p53 mRNA expression was similar between B-CLL groups and normal values and thus not related to clinical progression. However, since Bax alpha expression was lower in progressive than in non-progressive patients, the Bcl-2/Bax alpha ratio at the mRNA level was significantly higher in the progressive group. Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.
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PMID:Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression. 860 78

Cyclin A is a pivotal regulatory protein which, in mammalian cells, is involved in the S phase of the cell cycle. Transcription of the human cyclin A gene is cell cycle regulated through tight control of its promoter. We have previously shown that the ATF/CREB site, present in the cyclin A promoter, mediates transcriptional regulation by cAMP responsive element binding proteins. The main goal of the present study was to investigate whether this site is involved in transcriptional regulation of the gene. We have constructed stable NIH-3T3 cell lines that express the luciferase reporter gene under the control of normal or mutated versions of the cyclin A promoter. We show that the ATF/CREB is required to achieve maximal levels of transcription from the cyclin A promoter starting in late G1. We also show that down-regulation of the cyclin A promoter by p53 does not implicate a direct binding of p53 to its cognate consensus sequence but occurs probably by interference with trans-activating factors. This result suggests that p53 can interfere with transcription of the cyclin A gene, in the absence of a TATA sequence in the promoter.
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PMID:ATF/CREB site mediated transcriptional activation and p53 dependent repression of the cyclin A promoter. 864 61

There is no appropriate tumor marker for the selection of anti cancer drug. Some agents can be selected for the reversal of anti cancer drug resistance. For example, verapamil or cyclosporin A may be useful for p-glycoprotein related multidrug resistance, and amphotericin B, docosahexaenoic acid or 8-chloro cAMP can be used for the modification of cisplatin-resistance. Recently, bcl-2 or mutated p53 gene are demonstrated to be important markers for drug resistance. More studies are necessary to identify an appropriate markers for drug resistance and overcome it.
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PMID:[Selection of drugs for chemotherapy based on drug resistance marker]. 869 29

When human Bel-7402 hepatocarcinoma cell line grew in a medium containing 10(-4)M DDB, the secretion of alpha-fetoprotein (AFP) and the activity of gamma-glutamyl-transpeptidase (gamma-GT) were significantly lower than the control cells, whereas the albumin (ALB) secretion and the activity of tyrosine-alpha-ketoglutarate transaminase (TAT) were markedly increased. DDB at the concentration of 10(-4)M could significantly increase the content of cAMP in Bel-7402 cells, and also suppressed the expressions of oncogene c-myc and hepatocarcinoma marker AFP gene and enhanced the anti-oncogene p53 expression. The results of this paper suggest that DDB has some reversing effects on the phenotypes of human Bel-7402 hepatocarcinoma cell line.
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PMID:[Reversing effect of dimethyl-4,4'-dimethoxy-5,6,5'6'-dimethylenedioxybiphenyl-2,2'- dicarboxylate(DDB) on the phenotypes of human hepatocarcinoma cell line]. 869 89

In each menstrual cycle only very few follicles in the mammalian ovary undergo maturation and ovulation while most of the follicles degenerate in the process of atresia. Moreover, in the absence of pregnancy, the newly formed corpora lutea will degenerate and disappear in the process of luteolysis. Recent studies suggest that ovarian follicular atresia is associated with DNA fragmentation and degeneration of follicular cells, characteristics of programmed cell death (apoptosis). Apoptosis can be induced in vitro, in primary granulosa cell culture, by serum deprivation and by induction of a high intracellular level of cAMP. This induction of apoptosis can be blocked by fibroblast growth factor, suggesting that receptor-medicated activation of a tyrosine kinase can serve as a survival signal. Apoptosis can also be induced in immortalized steroidogenic granulosa cells, transformed by SV40 DNA and Ha-ras oncogene, by overexpression of the wild-type p53 tumor suppressor gene in cAMP-stimulated cells. Omitting the cAMP stimulus prevents the p53-induced apoptosis in these cells, suggesting cross-talk between p53 and c-AMP-generated signals in the induction of apoptosis. Steroidogenic activity in these cells, as well as in nontransformed granulosa cells, does not decline during apoptosis but is rather significantly elevated before total cell collapse occurs. Cytochemical studies using confocal laser microscopy, electron microscopy, and three-dimensional reconstruction reveal a specific reorganization pattern of proteasomes, the most abundant nonlysosomal protease, and of the steroidogenic organelles, such as mitochondria and lipid droplets, in the apoptotic cell. Our results suggest that compartmentalization of intracellular organelles during apoptosis permits proteolysis without interfering with steroidogenesis, characteristic of the differentiated phenotype of the granulosa cell. Moreover, cytoskeletal rearrangement may serve as a barrier between these cellular activities.
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PMID:Cross-talk between cAMP and p53-generated signals in induction of differentiation and apoptosis in steroidogenic granulosa cells. 873 10

Apoptosis can be initiated in immortalized cAMP-stimulated rat ovarian granulosa cells by induction of wild-type p53 activity. Immunocytochemical studies using confocal microscopy reveal that in apoptotic, unlike in normal growing cells, the proteasomes are removed from the nucleus and accumulate within the apoptotic blebs at the periphery of the cell. In parallel, a striking reorganization of the actin cytoskeleton is observed which forms a spherical network separating the apoptotic blebs from the cytoplasmic organelles, such as mitochondria and lipid droplets which remain in the perinuclear region. The reorganization of the actin cytoskeleton as well as disappearance of proteasomes from the nucleus suggest possible function of proteasomes in apoptotic regulation.
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PMID:Removal of proteasomes from the nucleus and their accumulation in apoptotic blebs during programmed cell death. 892 25

When human Bel-7402 hepatocarcinoma cell line grew in a medium containing 10(-4) M dimethyl-4,4'-dimethoxy-5,6,5', 6'-dimethylenedioxybiphynyl-2,2'-dicarboxylate (DDB), the secretion of alpha-fetoprotein (AFP) was significantly lower than the control cells, whereas the albumin (ALB) secretion was markedly higher. The activity of gamma-glutamultranspepeidase (gamma-GT) in DDB-treated cells markedly decreased in comparison with the control cells. On the contrary, the activity of tyrosine-alpha-ketoglutarate transaminase (TAT) was higher in DDB-treated cells than in control cells. DDB (10(-4) M) could significantly increase the content of cAMP in Bel-7402 cells, and also enhance the expression of anti-oncogene p53. The results suggest that DDB has reversing effects on the phenotypes of the human Bel-7402 hepatocarcinoma cell line.
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PMID:Reversing effect of dimethyl-4,4'-dimethoxy-5,6,5', 6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) on the phenotypes of human hepatocarcinoma cells line. 895 Feb 11

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a seco-steroid hormone with potential antitumoral activities, has been recently reported to exert cytotoxic effects on C6 glioma cells. However, the molecular mechanisms which trigger this cell death remain unknown. We show here that this 1,25(OH)2D3-induced cell death is dependent upon protein synthesis and is accompanied by the expression of c-myc, p53, and gadd45 genes. Two other genes, coding for interleukin-6 and vaso-endothelial growth factor, are also upregulated after addition of 1,25(OH)2D3. This programmed cell death can be suppressed when cells are treated with forskolin, a drug which increases intracellular cAMP concentration, or with genistein, an inhibitor of tyrosine protein kinases. However, in spite of the demonstration of fragmented DNA in 1,25(OH)2D3-treated cells, the C6.9 cells used in this study do not show the classical morphological features of apoptosis. These results provide the first evidence for the existence of a programmed cell death triggered by 1,25(OH)2D3 in glioma cells and may provide a basis for the development of new therapeutic strategies. In addition, these data also suggest that the treatment of C6.9 cells with 1,25(OH)2D3 may be a useful model to study the molecular mechanisms involved in the programmed cell death of a cell of glial origin.
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PMID:1,25-Dihydroxyvitamin D3 induces programmed cell death in a rat glioma cell line. 895 66

Bovine thyroglobulin gene upstream regulatory sequences were used as a tissue specific promoter in order to direct the expression of different genes specifically to the thyroid gland. Transgenic models of thyroid diseases have been generated, by directing the expression of specific oncogenes to the thyroid cell. In one of these models (TgAgT), the sv40 large T antigen promoted the development of an aggressive undifferentiated tumor mimicking the phenotype of the human anaplastic carcinoma. In the second model (TgA2aR), the expression of the adenosine A2 alpha receptor, acting as a constitutive activator of adenylyl cyclase, resulted in the development of a hyperfunctioning goiter, and in old animals to the formation of malignant foci. Transgenic lines expressing the E6 oncogenic (TgE6) from type 16 human papillomavirus appeared to be asymptomatic. In contrast, the thyroid cells of mice expressing E7 oncogene divide very rapidly, but remain differentiated, resulting in the development of huge colloid goiters. Signs of malignancy appear late in the development. The molecular properties of E6 and E7 oncogenes are to bind, and inactivatc, the tumor suppressor gene producers p53 (E6), or RB (E7). Our transgenic models indicate that the RB protein (and/or related proteins) are essential factors in the negative control of thyroid cell proliferation. On the contrary, inactivation of p53 seems to play a minor role, at least in the early steps of tumor formation. In the last model (Tg alpha 1B), the expression of a mutant of the alpha 1B adrenergic receptor reported to activate both CAMP and sigma P3-CA-cascades, resulted in growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals and malignancy.
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PMID:[Transgenic models of human thyroid pathologies: hyperfunctional adenoma, anaplastic cancer, differentiated cancer, hypothyroidism]. 900 25


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