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)

The topoisomerase inhibitors, camptothecin and etoposide target the activity of topoisomerase I and II respectively. These agents, or their analogues, are undergoing clinical trials for the treatment of metastatic breast cancer. In this study, we examined the response of eight breast epithelial cell lines, including six lines derived from breast cancers and two immortalized normal epithelial lines to camptothecin and etoposide. The lines varied by 700 fold in their sensitivity to the growth inhibiting effects of camptothecin and 30 fold in their response to etoposide. The BT474 line was the most resistant to both agents. The other cell lines did not have uniform sensitivity to both drugs, i.e., some lines were sensitive to one drug but relatively resistant to the other. A variety of parameters in these lines were analyzed to elucidate mechanisms of resistance including S phase, doubling time, expression and activity of topoisomerase I and II, expression of mdr-1, p53 status, cell cycle arrest, level of apoptosis, and expression of the apoptotic proteins Bcl-2 and Bax. We found that low levels of the topo I protein and its enzymatic activity were associated with increased resistance to camptothecin. This was not true for topo II activity and etoposide. Increased apoptotic responses were generally observed in cell lines that were sensitive to etoposide and this correlated with low ratios of Bcl-2/Bax protein. No single parameter was entirely predictive of response. However, the BT474 line displayed a series of characteristics including slow growth, the presence of mutant p53, low topo I activity, and a high Bcl-2/Bax ratio which together likely contributed to the resistance of this line to both etoposide and camptothecin.
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PMID:Complex response of breast epithelial cell lines to topoisomerase inhibitors. 971 86

The presence and distribution of apoptotic cell death in multiple system atrophy (MSA) and morphologically related diseases were investigated by means of a modified terminal deoxynucleotidyl transferase-mediated nick end labeling method, comparing their distribution with that of glial cytoplasmic inclusions, immunohistochemically demonstrated bcl-2 protein, bax protein, CD95, TNFalpha, and p53-protein expression, as well as activated microglia. Apoptosis occurred almost exclusively in oligodendrocytes in multiple system atrophy and its general distribution was comparable to the already known oligodendroglial pathology in this disorder. Additionally, in about a quarter of glial cytoplasmic inclusions, there was upregulation of bcl-2-protein and coexpression with ubiquitin, suggesting a final attempt of involved cells to counteract apoptotic cell death. Bax protein was also demonstrated in oligodendroglial cells. A significant neuronal apoptosis was not observed in MSA; these cells might be destroyed secondarily to oligodendroglial apoptosis by necrosis or other forms of programmed cell death. These results emphasize the central role of oligodendroglial pathology in multiple system atrophy, making this disease unique among neurodegenerative diseases.
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PMID:Cell death mechanisms in multiple system atrophy. 973 44

Homeostasis in colonic epithelial cells is regulated by the balance between proliferative activity and cell loss by apoptosis. Because epithelial cells at the apex of colonic crypts undergo apoptosis and proliferative activity is usually restricted to the base of the crypts, it has been proposed that the limited availability of growth factor-signals at the upper portions of the crypts may trigger apoptosis. In the present studies, we investigate the mechanism of apoptosis mediated by growth factor deprivation in colorectal carcinoma cells by delineating the possible involvement of Bax and its subcellular localization. We report that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase activity and downregulation of EGFR by anti-EGFR mAb 225 induces apoptosis in human colorectal carcinoma DiFi and FET cells. Induction of apoptosis was preceded by enhanced expression of newly synthesized Bax protein, and required protein synthesis. In the mAb 225-treated cells, Bax was redistributed from the cytosol to the nucleus and subsequently, to the nuclear membranes. The observed induction of Bax expression by mAb 225 was not associated with p53 induction. However, mAb 225 treatment also triggered relocalization of p53 from the cytosol to a nuclear membrane-bound form. Induction of Bax and its redistribution to the nucleus of DiFi cells during apoptosis was also demonstrated in response to butyrate, a physiological relevant molecule in colonic epithelial cells as it is the principal short-chain fatty acid produced by bacterial fermentation of dietary fiber in colonic epithelium. Using immunofluorescence and confocal microscopy, we observed that Bax is predominantly localized in the cytosol, but during apoptosis it is localized both inside and along the nuclear membrane. Taken together, these findings suggest that apoptosis induced by growth factor-deprivation or butyrate may involve the subcellular redistribution of Bax in human colorectal carcinoma cells.
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PMID:Nuclear targeting of Bax during apoptosis in human colorectal cancer cells. 974 79

Regulation of apoptosis is an important component of multistage hepatocarcinogenesis. The objectives of the present study were to characterize apoptosis regulation in primary mouse hepatocytes and to determine whether nongenotoxic carcinogens alter apoptosis regulation. Bleomycin-induced apoptosis was accompanied by decreases in bcl-2 and bcl-xl and increases in p53, bak, and bax protein levels. Transforming growth factor (TGF)-beta-induced apoptosis was accompanied by decreased bcl-xL and increased bak. Bleomycin-induced apoptosis was partially dependent on p53, whereas TGF-beta-induced apoptosis was independent of p53. Phenobarbital inhibited both TGF-beta and bleomycin-induced apoptosis and the normal regulation of p53, bcl-2, and bax. Nafenopin inhibited apoptosis through a mechanism dependent on PPAR-alpha and inhibited the normal regulation of bcl-2 and bak. 2,3,7,8-Tetrachlorodibenzo-p-dioxin did not alter apoptosis or its regulation. Apoptosis was increased in hepatocytes from bcl-2-null mice, which indicated that the bcl-2 family contributes to hepatocyte apoptosis regulation. This study demonstrated that apoptosis regulation in mouse hepatocytes involves distinct pathways and that diverse nongenotoxic carcinogens differentially alter molecular pathways that represent targets for hepatocarcinogenesis.
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PMID:Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens. 975 Nov 25

We have investigated several molecular events that occur during the process of tamoxifen-induced apoptosis in human breast carcinoma cells. We show that the treatment of either MCF-7 (containing wild-type p53) or MDA-MB-231 cells (containing mutant p53) with tamoxifen resulted in apoptotic nuclear changes and an increase in the pre-G1 apoptotic population. This was accompanied by activation of the caspase enzymes, as evidenced by specific cleavage of poly(ADP-ribose) polymerase and retinoblastoma (RB) protein. The RB protein was cleaved at both an interior and carboxyl terminus cleavage site. In addition, dephosphorylation of RB was found at an early stage of tamoxifen-induced apoptosis in both cell lines. However, neither induction of p53 in MCF-7 cells nor induction of p21 in either cell line was detected, suggesting that tamoxifen-induced RB dephosphorylation and apoptosis are independent of the p53/p21 pathway. We also observed an increase in levels of the pro-apoptotic Bax protein, the inhibitory cytokine TGF-beta1 and the transcription factor c-Myc in tamoxifen-treated MDA-MB-231 cells, suggesting the possible involvement of these proteins during apoptosis in this system.
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PMID:p53-independent dephosphorylation and cleavage of retinoblastoma protein during tamoxifen-induced apoptosis in human breast carcinoma cells. 975 Dec 62

The ability of lonidamine (LND), an energolytic derivative of indazole-carboxylic acid, to modulate the cytotoxicity of Taxol (TX) was investigated in the A2780 human ovarian cancer cell line. Different cytotoxicity results were obtained as a function of treatment schedule. Specifically, TX followed by LND produced synergistic effects. Conversely, antagonistic effects were recorded when drugs were given simultaneously or according to the opposite sequence. TX induced an oligonucleosomal DNA fragmentation typical of the apoptotic process. The extent and the kinetics of DNA cleavage in samples treated with the taxane alone were similar to those of samples treated with the TX-LND sequence. Activation of Yama protease and degradation of poly (ADP-ribose) polymerase were not observed after individual or combined treatment. LND did not appreciably modify the effect exerted by TX on proteins involved in cell cycle progression (i.e., inhibition of p34cdc2 expression) and apoptosis (i.e., upregulation of wt p53 and transactivation of p21waf1), and only caused a slight induction of the Bax protein. LND alone did not affect tubulin polymerization in A2780 cells and, when administered after a 24 hr TX exposure, did not appreciably alter the extent of tubulin polymerization induced by the taxane. Although additional studies are needed to define the molecular basis of the TX-LND interaction, our results suggest that LND can positively modulate the antitumor activity of TX in ovarian cancer cells and indicate that the energolytic is potentially useful in combination therapy including the taxane in ovarian cancer patients.
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PMID:Lonidamine as a modulator of taxol activity in human ovarian cancer cells: effects on cell cycle and induction of apoptosis. 976 75

The caspase-3 has been shown to be involved in mediating apoptosis induced by different stimuli. However, it is still unclear whether p53 is required for the ionizing radiation (IR)-induced caspase-3 activation. In the present study, we examined IR-induced apoptosis in three closely related human lymphoblast cell lines that differ in p53 status. Irradiation of TK6 cells (wild-type p53) with 4 Gy gamma-rays resulted in rapid apoptosis, whereas the apoptotic response was delayed and reduced in WTK1 cells (mutant p53) and the TK6 derivative line expressing HPV16 E6 (abrogated p53). The differential apoptotic responses in these cell lines correlated with caspase-3 activation. IR induced an early as well as a late phase of caspase-3 activation in TK6 but only a delayed onset in WTK1 and TK6-E6-5E cells. The early phase of caspase-3 activation coincided with an elevation of p53 and bax protein levels. Pretreatment of all three cell lines with a caspases inhibitor z-VAD-FMK inhibited apoptosis. These results suggest that IR-induced apoptosis is mediated by a mechanism involving the caspase-3 cascade, which is shared by both p53-dependent and -independent pathways. The activation of caspase-3 by IR may thus engage at least two separate mechanisms, one through the regulation of the bcl-2 family members by p53, whereas the other yet-to-be-identified one involves neither p53 nor bax.
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PMID:p53 is involved in but not required for ionizing radiation-induced caspase-3 activation and apoptosis in human lymphoblast cell lines. 976 52

The following phases of apoptosis were proposed: decisive, executive and degradation. At least two checkpoints are recognized in the process of apoptosis: the p53 and Bcl-2/Bax protein family checkpoint and the protease-caspase and serine protease checkpoint. Signals to apoptosis from outside of the cell including Fas and Fas ligand interaction and sphingomyelin cycle were presented. Cellular morphological events in apoptosis: DNA chain breaks, changes in cell membrane and mitochondrial membranes were discussed. Some medical problems of cardiology in which apoptosis plays an important role were presented. The cancer treatment results depending on apoptosis of cancer cells were discussed as well.
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PMID:Apoptosis and some of its medical implications. 977 93

Susceptibility of a tumor cell to undergo chemotherapy-induced apoptosis appears to be dependent upon the balance of proapoptotic and survival factors that are expressed within any given cell. We have chosen to evaluate how expression of several of these proteins influences chemosensitivity of a panel of 10 pediatric tumor cell lines chosen from three tumor histiotypes: neuroblastoma, rhabdomyosarcoma, and pediatric glial tumors. The proteins evaluated were p53 and six members of the Bax/Bcl-2 family: three proapoptotic proteins (Bax, Bak, and Bcl-xS) and three survival factors (Bcl-2, Bcl-xL, and Mcl-1). We investigated whether there was any relationship between endogenous expression of these proteins and chemosensitivity (or resistance) to three chemotherapeutic agents that directly damage DNA (doxorubicin, actinomycin D, and topotecan) and a mitotic spindle poison (vincristine). Even though exogenous overexpression of wild-type p53 has been associated with a chemosensitive phenotype in several model systems we demonstrated no such relationship in these studies. In addition, expression levels of Bcl-2, Bcl-xL, Bcl-xS, Bak, or Mcl-1 did not correlate with sensitivity or resistance to the four drugs. However, there was a statistically significant correlation between endogenous levels of Bax protein and sensitivity to both doxorubicin and actinomycin D. We conclude that even though many proteins such as p53 and Bcl-2 have been shown to influence drug response when exogenously overexpressed in model systems, in unmodified cell lines endogenous protein levels may not generate the same results. We have demonstrated that endogenous Bax expression was the only protein found to be associated with chemosensitivity across the three different tumor histiotypes and propose that analysis of Bax may be a more useful prognostic indicator for tumor response to therapy than either p53 or Bcl-2.
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PMID:Bax is an important determinant of chemosensitivity in pediatric tumor cell lines independent of Bcl-2 expression and p53 status. 980 58

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.
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PMID:p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. 985 25


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