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)

Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.
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PMID:Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines. 1504 34

Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are potent immunosuppressive environmental contaminants acting on lymphocytes and monocytes. To establish whether differentiated macrophages, which play a crucial role in innate and acquired immunity, can also constitute major cellular targets, we have characterized PAH effects towards primary human macrophages. BP-treatment was found to dramatically alter their functional capacities and to trigger a caspase- and mitochondrion-related apoptosis, associated with down-regulation of the survival factors c-FLIP(L) and Bcl-X(L) and up-regulation of the pro-apoptotic factor p53. Such deleterious effects were associated with BP metabolite production, whose inhibition by the cytochrome P-450 1A1 inhibitor alpha-naphthoflavone fully abolished BP toxicity. In contrast to BP, the related halogenated arylhydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin, known to be poorly metabolized if any, only minimally affected macrophages. Overall, these data provide evidence for a cytochrome P-450-dependent toxicity of PAHs towards human differentiated macrophages, which may contribute to their immunosuppressive effects.
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PMID:Cytochrome P450-dependent toxicity of environmental polycyclic aromatic hydrocarbons towards human macrophages. 1508 98

Shikonin is a main constituent of the roots of Lithospermum erythrorhizon that has antimutagenic activity. However, its other biological activities are not well-known. Shikonin displayed a strong inhibitory effect against human colorectal carcinoma COLO 205 cells and human leukemia HL-60 cells, with estimated IC(50) values of 3.12 and 5.5 microM, respectively, but were less effective against human colorectal carcinoma HT-29 cells, with an estimated IC(50) value of 14.8 microM. Induce apoptosis was confirmed in COLO 205 cells by DNA fragmentation and the appearance of a sub-G1 DNA peak, which were preceded by loss of mitochondrial membrane potential, reactive oxygen species (ROS) generation, cytochrome c release, and subsequent induction of pro-caspase-9 and -3 processing. Cleavages of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor (DFF-45) were accompanied by activation of caspase-9 and -3 triggered by shikonin in COLO 205 cells. Here, we found that shikonin-induced apoptotic cell death was accompanied by upregulation of p27, p53, and Bad and down-regulation of Bcl-2 and Bcl-X(L), while shikonin had little effect on the levels of Bax protein. Taken together, we suggested that shikonin-induced apoptosis is triggered by the release of cytochrome c into cytosol, procaspase-9 processing, activation of caspase-3, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by shikonin may provide a pivotal mechanism for its cancer chemopreventive action.
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PMID:Induction of apoptosis by shikonin through coordinative modulation of the Bcl-2 family, p27, and p53, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells. 1545 9

The activated hepatic stellate cell (HSC) is an important fibrogenic cell type of the liver. Interferon-alpha (IFN-alpha) has recently been shown to elicit an antiapoptotic effect on activated HSC by a JAK-2-dependent inhibition of caspase-8 activation. As JAK-2 has so far been shown to be a member of the IFN-gamma signal transduction pathway we studied the effect of IFN-gamma on apoptosis as well as on its signaling in primary cultured rat HSC. IFN-gamma elicited a proapoptotic effect in activated HSC. The combination of both, IFN-gamma and IFN-alpha, however, completely cancelled each other's effect. No effect of the two cytokines on major members of apoptosis-regulating systems (CD95, CD95L, bcl-2, bax, bcl-xL, p53, p21WAF1, p27, NFkappaB) could be observed. Western Blot analysis revealed that gene expression of the chaperone HSP70 was found to be downregulated by IFN-gamma but upregulated by IFN-alpha. The effect could be abrogated by administration of both. After transfection of activated HSC with a pCMV-HSP70 M expression vector the proapoptotic effect of IFN-gamma was cancelled. Using HSP70 antisense, the antiapoptotic effect of IFN-alpha was cancelled as well. However IFN-gamma had no effect on upregulation of JAK-2 and pJAK-2 by IFN-alpha. Taken together IFN-gamma and IFN-alpha exert opposite effects on apoptosis in HSC. This effect is mediated by their counteracting effect on HSP70 expression which acts antiapoptotic at the level of caspase-8.
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PMID:Interferon-gamma acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway. 1554 Apr 63

Enhanced expression of the apoptosis-preventing protein bcl-xL and the cell cycle-regulating protein p21 was observed in bone marrow infiltrates of systemic mastocytosis. Expression of bcl-2, Ki67, and p53 as well as ISEL apoptosis staining were comparable in patients with mastocytosis and in controls. An altered rate of apoptosis and cell cycling may contribute to accumulation of mast cells in mastocytosis.
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PMID:Altered apoptosis and cell cycling of mast cells in bone marrow lesions of patients with systemic mastocytosis. 1559 Apr 5

Neuroblastoma is a pediatric tumor accounting for 15% of childhood cancer deaths and has a poor prognosis in children >1 year of age. We investigated the ability of apigenin, a nonmutagenic dietary flavonoid that has been shown to have antitumor effects in various tumor cell lines, to inhibit growth and induce apoptosis of the human neuroblastoma cell lines NUB-7, LAN-5, and SK-N-BE(2). Apigenin inhibited colony-forming ability and survival, and induced apoptosis of NUB-7 and LAN-5 cells. The presence of the C2-C3 double bond and the 4'-OH group on the flavonoid structure correlated with the growth-inhibitory potential of apigenin. Furthermore, apigenin inhibited NUB-7 xenograft tumor growth in anonobese diabetic/severe combined immunodeficiency mouse model, likely by inducing apoptosis. Apigenin did not inhibit survival of primary sympathetic neurons, suggesting that it is not toxic to nontransformed cells. The mechanism of action of apigenin seems to involve p53, as it increased the levels of p53 and the p53-induced gene products p21WAF1/CIP1 and Bax. Furthermore, apigenin (15-60 micromol/L) induced cell death and apoptosis of neuroblastoma cells expressing wild-type but not mutant p53. Apigenin increased caspase-3 activity and PARP cleavage, and Z-VAD-FMK, a broad-spectrum caspase-3 inhibitor, rescued NUB-7 cells from apigenin-mediated apoptosis indicating that apigenin induced apoptosis in acaspase-dependent manner. Overexpression of Bcl-X(L) rescued NUB-7 from apigenin-induced cell death, suggesting that Bax activity is important for the action of apigenin. Apigenin is thus a candidate therapeutic for neuroblastoma that likely acts by regulating a p53-Bax-caspase-3 apoptotic pathway.
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PMID:Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. 1565 48

Farnesyltransferase inhibitor (FTI) acts on ras, which can ultimately enhance radiosensitivity. The objective of this study was to explore whether FTI could potentiate the antitumor efficacy of radiation in vivo, particularly in radio-resistant hepatocarcinomas (HCa-I) syngeneic to C3H/HeJ mice. The presence of ras mutations was examined by PCR and DNA sequencing. C3H/HeJ mice, bearing HCa-I, were treated with FTI, LB42907, and 25 Gy radiation. FTI was orally administered, 60 mg/kg, twice daily for 30 days. The expression of regulating molecules was analyzed by Western blotting for p53, p21(WAF1/CIP1), and the Bcl-2 family, such as Bcl-2, Bax, and Bcl-X(L/s). In HCa-I, no ras mutations were detected. Downregulation of ras by FTI was most prominent at 4 h after treatment. In a tumor growth delay assay, FTI increased the effect of the tumor's radioresponse, with an enhancement factor of 1.32. Combined irradiation and FTI increased radiation-induced apoptosis; the peak apoptotic index was 3.6% with irradiation alone and with the drug alone but 7.1% in the combined treatment group. The analysis of apoptosis-regulating molecules by Western blotting showed upregulation of p53 and p21(WAF1/CIP1) in the combined treatment group compared with those in either of the single treatment groups, but the Bcl-2 family remained unchanged. FTI, in combination with radiation therapy, may have potential benefits in cancer treatment even if there are no ras mutations. FTI could inhibit ras activity but may also affect any protein that requires farnesylation for its activity.
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PMID:Enhancement of tumor response by farnesyltransferase inhibitor in C3H/HeJ hepatocarcinoma. 1565 85

Molecular parameters involved in the prediction of response of childhood acute lymphoblastic leukemia (ALL) are still unclear. We have evaluated the expression and mutational status of p53 and the expression of bcl-x(L) and bax in a series of 62 consecutive children (median age: 4 years; 38 males and 24 females) affected by de novo ALL. Alterations and overexpression of p53 were uncommon events (9/62, 14.5%) while bcl-x(L) and bax overexpression were frequent (about 70%). EFS was directly correlated to age<6 years (p=0.0178), nonT phenotype (p=0.0470), WBC at diagnosis<or=20000/microl (p=0.0093), response to induction therapy with prednisone (p=0.0211) and inversely correlated to mutated p53 or overexpression of p53 (p=0.0039) and high intensity of Bcl-xL expression (p=0.0055). OS was directly correlated with age<6 years (p=0.0004), female gender (p=0.0139), nonT phenotype (p=0.0012), WBC at diagnosis<or=20000/microl (p=0.0187), response to induction therapy with prednisone (p=0.0211), wild type p53 or low expression of p53 (p=0.035). When all factors were considered in a stepwise Cox regression analysis, only the good response to PDN (p=0.013) and the low intensity of Bcl-xL expression (p=0.001) were independent significant prognostic factors with regard to EFS. Moreover, only age (p=0.022), gender (p=0.036) and WBC at the diagnosis (p=0.050) were independent prognostic factors with regard to OS. Moreover, the mutated status of p53 was statistically correlated to the resistance to the induction therapy with PDN (correlation coefficient: -0.349, p=0.008). In conclusion, both bcl-xL and bax were frequently expressed at high intensity, but only bcl-xL was an independent predictor of EFS in our series. Moreover, p53 alterations were uncommon and alone not strong independent predictors of outcome, but they were correlated to poor response to therapy with PDN and inversely correlated to EFS and OS in univariate analysis.
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PMID:Prognostic role of bcl-xL and p53 in childhood acute lymphoblastic leukemia (ALL). 1568 3

The fruiting body of Antrodia camphorata is well known in Taiwan as a traditional medicine for treating cancer and inflammation. The purpose of this study was to evaluate the apoptotic effects of ethylacetate extract from A. camphorata (EAC) fruiting bodies in two human liver cancer cell lines, Hep G2 and PLC/PRF/5. Treatment with EAC decreased the cell growth of Hep G2 and PLC/PRF/5 cells in a dose dependent manner. In Fas/APO-1 positive-Hep G2 cells, EAC increased the expression level of Fas/APO-1 and its two forms of ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), in a p53-indenpendent manner. In addition, EAC also initiated mitochondrial apoptotic pathway through regulation of Bcl-2 family proteins expression, release of cytochrome c, and activation of caspase-9 both in Hep G2 and PLC/PRF/5 cells. Furthermore, EAC also inhibited the cell survival signaling by enhancing the amount of IkappaBalpha in cytoplasm and reducing the level and activity of NF-kappaB in the nucleus, and subsequently attenuated the expression of Bcl-X(L) in Hep G2 and PLC/PRF/5 cells. EAC therefore decreased the cell growth and induced apoptosis both in Hep G2 and PLC/PRF/5 cells.
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PMID:Apoptotic effects of extract from Antrodia camphorata fruiting bodies in human hepatocellular carcinoma cell lines. 1579 30

Zeocin, a member of the bleomycin/phleomycin family of antibiotics, is known to bind DNA and to induce apoptosis in cervical cancer cells, but the mechanism underlying this apoptotic response is poorly understood. The present study was undertaken to elucidate time-dependent serial transcript patterns in the HeLa cervical carcinoma cell line, following treatment with Zeocin. The HeLa cell proliferation rate was found to gradually decrease following Zeocin exposure, in a time-and dose-dependent manner. RNA transcript level measurements, for time-dependent serial gene expression profiling, were determined at 0, 6, 12, 18 and 24 hr using a 0.5 k apoptosis functional microarray chip. Further statistical analysis, using a significance test at a 95% confidence level, for transcripts with a greater than 2-fold change on the array chips, identified 49 up-regulated and 57 down-regulated genes. Our gene expression profile data indicate that Zeocin treatment induces an initial release of cytochrome c, the down-regulation of Bcl-X (L), ENDOG, DAXX and MDM2, and the up-regulation of CASP and BID. This suggests that a p53-independent mitochondrial caspase cascade pathway is primarily involved in Zeocin-induced apoptosis. Such caspasedependent cytotoxic activity also implies that this cell death pathway occurs via the caspase 8 and BID genes. However, disruption of either FAS or TNFR1 signaling did not interfere with the Zeocin induced apoptotic response in our experimental system. We hypothesize that Zeocin could be active against cervical cancer cell resistance to conventional chemotherapy and postulate that Zeocin is a novel candidate for the development of new chemotherapeutic treatments of gynecological cancers.
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PMID:The time-dependent serial gene response to Zeocin treatment involves caspase-dependent apoptosis in HeLa cells. 1584 Sep 58


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