Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD95 (Fas/APO-1) system regulates a number of physiological and pathological processes of cell death. The ligand for CD95 induces apoptosis in sensitive target cells by interacting with a transmembrane cell surface CD95 receptor. We previously reported that the recombinant adenovirus-mediated transfer of the wild-type p53 gene caused apoptotic cell death in a variety of human cancer cells. To better understand the mechanism responsible for this cell death signaling, we have investigated the potential involvement of the CD95 receptor/ligand system in p53-mediated apoptosis. The transient expression of the wild-type p53 gene upregulated the CD95 ligand mRNA as well as protein expression in H1299 human lung cancer cells deficient for p53 and in DLD-1 and SW620 human colon cancer cells with mutated p53, all of which constitutively expressed CD95 receptor as shown by a flow cytometric analysis, and induced rapid apoptotic cell death as early as 24 h after gene transfer. However, the sensitivity to the cytolytic effect of agonistic anti-CD95 antibody (CH11) varied among these cell lines: CH11 induced apoptosis in H1299 cells, but not in DLD-1 and SW620 cells despite their abundant CD95 receptor expression, suggesting that the CD95 receptors on DLD-1 and SW620 cells might be inactivated. In addition, an antagonistic anti-CD95 ligand antibody (4H9) that interfered with the CD95-receptor-ligand interaction partially reduced the apoptosis induced by the wild-type p53 gene transfer in H1299 cells, whereas apoptosis of DLD-1 and SW620 cells occurred in the presence of 4H9. Taken together, these findings led us to conclude that the CD95 receptor/ligand system is differentially involved in p53-mediated apoptosis, suggesting that the restoration of the wild-type p53 function may mediate apoptosis through CD95 receptor/ligand interactions as well as an alternative pathway.
 ...
PMID:Differential involvement of the CD95 (Fas/APO-1) receptor/ligand system on apoptosis induced by the wild-type p53 gene transfer in human cancer cells. 1032 65

Betulinic acid (BA), a pentacyclic triterpene, is an experimental cytotoxic agent for malignant melanoma. Here, we show that BA triggers apoptosis in five human glioma cell lines. BA-induced apoptosis requires new protein, but not RNA, synthesis, is independent of p53, and results in p21 protein accumulation in the absence of a cell cycle arrest. BA-induced apoptosis involves the activation of caspases that cleave poly(ADP ribose)polymerase. Interactions of death ligand/receptor pairs of the CD95/CD95 ligand family do not mediate BA-induced caspase activation. BA enhances the levels of BAX and BCL-2 proteins but does not alter the levels of BCL-xS or BCL-xL. Ectopic expression of BCL-2 prevents BA-induced caspase activation, DNA fragmentation, and cell death. Furthermore, BA induces the formation of reactive oxygen species that are essential for BA-triggered cell death. The generation of reactive oxygen species is blocked by BCL-2 and requires new protein synthesis but is unaffected by caspase inhibitors, suggesting that BA toxicity sequentially involves new protein synthesis, formation of reactive oxygen species, and activation of crm-A-insensitive caspases.
 ...
PMID:Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing. 1033 21

The temperature-sensitive murine p53val135 mutant was introduced into 3 human malignant glioma cell lines to examine the effects of the p53 status on BCL-2 family protein expression, CD95 expression, and sensitivity to CD95 ligand (CD95L)-induced apoptosis. p53val135 behaves as a dominant negative mutant at 38.5 degrees C but assumes p53 wild-type properties. In order to dissect (i) specific effects of wild-type versus mutant p53, and (ii) transdominant-negative versus gain-of-function effects of mutant p53, we included glioma cell lines with functional wild-type (LN-229), mutant (LN-18) or deleted (LN-308) p53 genes. Wild-type, but not mutant, p53val135 promoted G2/M arrest and accumulation of BAK protein in all cell lines. The levels of other BCL-2 family members including BAX, BCL-2, BCL-X or MCL-1 were not consistently modulated by mutant or wild-type p53val135. Wild-type, but not mutant, p53val135 enhanced CD95 expression in all cell lines. CD95L-evoked caspase 3 activity was unaffected by wild-type p53 in all cell lines. Unexpectedly, mutant p53val135 differentially modulated caspase 3 activity in a gain-of-function fashion in that caspase 3 activity induced by CD95L was enhanced in LN-229 and LN-308 cells but reduced in LN-18 cells. Yet, mutant p53val135 enhanced the sensitivity to CD95L in LN-18 cells, had no effect in LN-229 cells, and decreased the sensitivity of LN-308 cells. Corresponding to the unaltered CD95L-evoked caspase 3 activity, wild-type p53val135 had no major effect on CD95L-induced apoptosis, except for a moderate sensitization of LN-229 cells but only when protein synthesis was inhibited. Thus, wild-type p53 induces BAK and CD95 expression in human glioma cells without enhancing their susceptibility to CD95-mediated apoptosis, and mutant p53 modulates CD95L-evoked apoptotic signalling in a gain-of-function fashion up-stream and down-stream of caspase 3 activation.
 ...
PMID:p53 enhances BAK and CD95 expression in human malignant glioma cells but does not enhance CD95L-induced apoptosis. 1035 42

Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.
 ...
PMID:Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity. 1036 Jun 53

Glial fibrillary acidic protein (GFAP)-v-src transgenic mice develop spontaneous gliomas with a high incidence of malignant progression. We characterize the first glial cell line derived from v-src transgenic mice, Tu-2449 in comparison with a virally induced murine glioma, SRB-10, and a spontaneous murine glioma, P497. Doubling times were lowest, as clonogenicity in soft agar was highest for Tu-2449, and to a lesser degree, Tu-2449 cells formed spheroids and showed migratory behaviour and invaded fetal rat brain aggregates. BCL-2 and BAX expression were lower in Tu-2449 and P497 than in SRB-10 cells. Only Tu-2449 cells accumulated p53 protein in response to genotoxic stress. Tu-2449 and SRB-10 cells that showed low CD95 expression were resistant to CD95 ligand (CD95L)-induced apoptosis unless coexposed to CD95L and inhibitors of RNA or protein synthesis. A chemosensitivity profile revealed Tu-2449 to be rather chemoresistant. Tu-2449 thus displays growth characteristics and patterns of resistance to apoptosis similar to those of other mouse and human glioma cell lines and may therefore become a valuable tool to evaluate new therapies for malignant gliomas in vitro and in vivo.
 ...
PMID:Characterization of Tu-2449, a glioma cell line derived from a spontaneous tumor in GFAP-v-src-transgenic mice: comparison with established murine glioma cell lines. 1049 69

We examined the effect of paclitaxel on human osteoblastic cells Saos-2 to determine if paclitaxel can affect proliferation and apoptosis. We used a p53-negative cell line in order to mimic the loss of function frequently observed at the clinical level. Paclitaxel induced cell death in a dose- and time-dependent manner. Marked nuclear condensation and fragmentation of chromatin were observed by Hoechst 33258 stain, DNA ladder formation, electron microscopy, and flow cytometry at concentrations as low as 100 nM, a concentration which can be achieved by infusion in human plasma. At 100 nM, paclitaxel induced a G2 arrest at 8 h of treatment. The cells then continued to accumulate in G2 until 72 h when the percentage of apoptotic events reached 54%. At the molecular level, Bcl-2 protein was phosphorylated at 16 h and PARP protein was cleaved, indicating the activation of caspase-3-like proteases. Caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK rescued Saos-2 cells from paclitaxel-induced apoptosis. CD95 expression was constantly high, while CD95L showed a threefold increase in expression. This suggests that, following the G2 arrest, apoptosis is induced through the CD95/CD95L system.
 ...
PMID:Paclitaxel induces apoptosis in Saos-2 cells with CD95L upregulation and Bcl-2 phosphorylation. 1050 6

The observations presented in this paper indicate that serum of Dalton's lymphoma (DL) bearing mice contained certain soluble factor(s) that augmented the induction of apoptosis in thymocytes in a time- and dose-dependent manner. DL-ascitic fluid and DL-conditioned medium could also induce apoptosis of thymocytes in vitro, though the magnitude of the same was consistently lower than that induced by serum of DL-bearing mice. It was observed that the interaction of FasL and TNFalpha with their respective receptors could trigger apoptosis in thymocytes. Elucidation of the signal transduction mechanism revealed involvement of protein tyrosine kinase, protein kinase C and ser/thr phosphatases with concomitant increase in the level of protein products of apoptosis associated genes p53, bax, bad, fas and fas ligand and cleavage of N-terminal 23 kDa fragment of Bcl-2 that exhibited Bax-like death effector properties. Further, we report, for the first time, the ability of thymosin alpha-1, an immunopotentiating thymic hormone, to antagonize apoptosis in thymocytes induced by factors present in serum of DL-bearing mice. The underlying mechanism of tumor serum induced apoptosis inhibition by thymosin alpha-1 was also analyzed. The signal transduction cascade evoked by thymosin alpha-1 involves activation of protein kinase C with a decrease in the level of protein products of proapoptotic genes like bax and bad and increase in the protein products of bcl-2 gene.
 ...
PMID:Mechanism of thymocyte apoptosis induced by serum of tumor-bearing host: the molecular events involved and their inhibition by thymosin alpha-1. 1068 4

Molecular mechanisms of basal and D-amphetamine (AMPH)-induced apoptosis were studied in rat liver nodules, 12 (N12) and 30 (N30) weeks after initiation, and in hepatocellular carcinoma (HCC) induced by diethylnitrosamine in rats subjected to resistant hepatocyte model. Basal apoptosis in hematoxylin/eosin- and propidium iodide-stained sections was higher in nodules and HCC than in normal livers. It sharply increased in all tissues 4 hours after AMPH treatment (10 mg/kg), and declined to basal levels at 8 to 12 hours in liver and N12, but remained high up to 18 hours in N30 and HCC. c-myc, Tgf-alpha, p53, and Bcl-X(S) messenger RNA (mRNA) levels were higher, and Bcl-2 mRNA was lower in N12 and/or N30 and HCC than in normal liver. Four hours after AMPH injection, increase in c-myc and decreases in Bcl-2 and Bcl-X(L) mRNAs occurred in all tissues, whereas p53, Bax, and Bcl-X(S) mRNAs increased in N30 and HCC. These changes disappeared in liver and N12 at 18 hours, but persisted in N30 and HCC. c-Myc, P53, Bcl-2, and Bax proteins in normal liver and HCC +/- AMPH showed similar patterns. Tgf-beta1, Tgf-beta-RIII, CD95, and CD95L mRNA levels underwent slight or no changes in any tissue +/- AMPH. Basal Hsp27 expression was high in nodules and HCC, and was stimulated by AMPH in liver and N12, but not in N30 and HCC. These data suggest a role of dysregulation of Bcl-2 family genes and, at least in atypical lesions, of p53 overexpression, in basal and AMPH-induced apoptosis in nodules and HCCs. Hsp27 does not appear to sufficiently protect atypical lesions against apoptosis.
 ...
PMID:Implication of Bcl-2 family genes in basal and D-amphetamine-induced apoptosis in preneoplastic and neoplastic rat liver lesions. 1073 53

The pronounced resistance of human renal cell carcinoma (RCC) to anticancer-induced apoptosis has primarily been related to the expression of P-glycoprotein and effective drug detoxification mechanisms. Because the CD95 system has recently been identified as a key mediator of anticancer drug-induced apoptosis, we analysed the contribution of the CD95 system to chemotherapy-induced apoptosis in four newly established RCC cell lines. Here, we demonstrate that all RCC cell lines expressed CD95-receptor and -ligand. Exposure to agonistic anti-CD95 antibodies resulted in induction of apoptosis and significant (P < 0.05) reduction of cell number in three out of four cell lines, indicating that the essential components for CD95-mediated apoptosis were present and functionally intact in the majority of these RCC cell lines. Moreover, treatment of cultures with bleomycin or topotecan, a novel topoisomerase I inhibitor with little substrate affinity for P-glycoprotein, led to induction of apoptosis and significant (P < 0.05) dose-dependent reduction of cell number in all RCC cell lines. Both anticancer drugs also induced upregulation of CD95 ligand expression in all cell lines. Additionally, augmentation of CD95 receptor expression was found in three RCC cell lines, including one p53-mutated cell line, whereas another p53-mutated cell line showed no or only a weak CD95 receptor upregulation after exposure to topotecan or bleomycin, respectively. Despite this upregulation of CD95 receptor and ligand, antagonistic antibodies directed against CD95 receptors or ligands could not inhibit induction of apoptosis by topotecan and bleomycin in any cell line. Thus, although a functionally intact CD95 signalling cascade is present in most RCC cell lines, the anticancer drugs topotecan and bleomycin that induce upregulation of CD95 receptor and ligand fail to effectively activate CD95-mediated apoptosis. This deficient activation of CD95-mediated apoptosis might be an important additional factor for the multidrug resistance phenotype of human RCCs.
 ...
PMID:Deficient activation of CD95 (APO-1/Fas)-mediated apoptosis: a potential factor of multidrug resistance in human renal cell carcinoma. 1083 1

CM101, a bacterial polysaccharide exotoxin produced by group B Streptococcus (GBS), also referred to as GBS toxin, has been shown to target pathological neovasculature and activate complement (C3), thereby inducing neovascularitis, infiltration of inflammatory cells, inhibition of tumor growth, and apoptosis in murine tumor models. Data from refractory cancer patients in a Phase I clinical trial with CM101 indicated a similar mechanism of tumor-targeted inflammation. To further our understanding of the mechanism of action of CM101 as an antitumor agent, we examined the role of the inflammatory response in inducing tumor apoptosis in a normal mouse and tumor-bearing mouse model. The i.v. infusion of CM101 into B16BL-6 melanoma tumor-bearing mice elevated p53 mRNA in circulating leukocytes as measured by reverse transcription-PCR, and immunohistochemistry demonstrated infiltration and sequestration of leukocytes. Whole tumor lysates from excised tumors exhibited an increase in binding to the murine p21(Waf1/Cip1) derived p53 DNA binding sequence compared with control whole tumor lysates, in which minimal or no DNA binding was observed. CM101 infusion led to elevated levels of Fas protein within the tumors as well as a decrease in the expression of fas ligand (fasL). Furthermore, tumors were apoptotic as determined by terminal deoxynucleotidyl transferase-mediated nick end labeling and DNA fragmentation assays. Collectively, these data suggest that CM101 up-regulates p53 in tumor-infiltrating leukocytes, initiating a loss of tumor immunoprivilege and consequently rendering the tumor sensitive to Fas/fasL-mediated apoptosis. CM101 induced loss of tumor immunoprivilege through changes in the expression of leukocyte p53, tumor Fas and fasL coupled with neovascularitis and leukocyte infiltration, constitutes a plausible molecular pathway for tumor reduction observed in cancer patients.
 ...
PMID:CM101 treatment overrides tumor-induced immunoprivilege leading to apoptosis. 1105 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>