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)

Acacetin (5,7-dihydrocy-4'-methoxy flavone), which is a flavonoid compound, possesses anti-peroxidative and anti-inflammatory effects. The effects of acacetin on cell viability in human gastric carcinoma AGS cells were investigated. This study demonstrated that acacetin was able to inhibit cell proliferation and induce apoptosis in a concentration- and time-dependent manner. Acacetin-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation, and cell morphology. The molecular mechanism of acacetin-induced apoptosis was also investigated. Treatment with acacetin caused induction of caspase-3 activity in a time-dependent manner, but not caspase-1 activity, and induced the degradation of DNA fragmentation factor (DFF-45) and poly(ADP-riobse) polymerase. Cell death was completely prevented by a pancaspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone. Furthermore, treatment with acacetin caused a rapid loss of mitochondrial transmembrane potential, stimulation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. Antioxidants such as N-acetylcysteine and catalase, but not superoxide dismutase, allopurinol, or pyrrolidine dithiocarbamate, significantly inhibited acacetin-induced cell death. In addition, it was found that acacetin promoted the up-regulation of Fas and FasL prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement of a Fas-mediated pathway in acacetin-induced apoptosis. On the other hand, the results showed that acacetin-induced apoptosis was accompanied by up-regulation of Bax and p53, down-regulation of Bcl-2, and cleavage of Bad. Taken together, these results suggest that ROS production and a certain intimate link might exist between receptor- and mitochondria-mediated death signalings that committed to acacetin-induced apoptosis in AGS cells. The induction of apoptosis by acacetin may provide a pivotal mechanism for its cancer chemopreventive action.
 ...
PMID:Acacetin induces apoptosis in human gastric carcinoma cells accompanied by activation of caspase cascades and production of reactive oxygen species. 1568 11

Pseudolaric acid B is a major compound found in the bark of Pseudolarix kaempferi Gordon. In our study, pseudolaric acid B inhibited growth of human melanoma cells, A375-S2 in a time- and dose-dependent manner. A375-S2 cells treated with pseudolaric acid B showed typical characteristics of apoptosis including morphologic changes, DNA fragmentation, sub-diploid peak in flow cytometry, cleavage of poly-ADP ribose polymerase (PARP) and degradation of inhibitor of caspase-activated DNase (ICAD). P53 protein expression was upregulated while cells were arrested at the G2/M phase of the cell cycle. There was a decrease in the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins, whereas pro-apoptotic Bax was increased. The two classical caspase substrates, PARP and ICAD, were both decreased in a time-dependent manner, indicating the activation of downstream caspases.
 ...
PMID:Pseudolaric acid B induces apoptosis through p53 and Bax/Bcl-2 pathways in human melanoma A375-S2 cells. 1574 11

The p53 binding protein 2 (53BP2) has been identified as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). The TP53BP2 gene encodes two splicing variants, 53BP2S and 53BP2L, previously known as apoptosis stimulating protein 2 of p53 (ASPP2). We found that these 53BP2 proteins are located predominantly in the cytoplasm and induce apoptosis as demonstrated by cleavage of poly ADP ribose polymerase (PARP) and annexin V staining. Furthermore, we demonstrate that 53BP2 is located in the mitochondria and induces apoptosis associated with depression of the mitochondrial trans-membrane potential (DeltaPsim) and activation of caspase-9. From these findings we conclude that 53BP2 induces apoptosis through the mitochondrial death pathway.
 ...
PMID:53BP2 induces apoptosis through the mitochondrial death pathway. 1574 14

The cardiotoxicity of adriamycin limits its clinical use as a powerful drug for solid tumors and malignant hematological disease. Although the precise mechanism by which it causes cardiac damage is not yet known, it has been suggested that apoptosis is the principal process in adriamycin-induced cardiomyopathy, which involves DNA fragmentation, cytochrome C release, and caspase activation. However, there has been no direct evidence for the critical involvement of caspase-3 in adriamycin-induced apoptosis. To determine the requirements for the activation of caspase-3 in adriamycin-treated cardiac cells, the effect of a caspase inhibitor on the survival of and apoptotic changes in H9c2 cells was examined. Exposure of H9c2 cells to adriamycin resulted in a time- and dose-dependent cell death, and the cleavage of pro-caspase-3 and of the nuclear protein poly (ADP'ribose) polymerase (PARP). However, neither the reduction of cell viability nor the characteristic morphological changes induced by adriamycin were prevented by pretreatment with the general caspase inhibitor z-VAD.FMK. In contrast, caspase inhibition effectively blocked the apoptosis induced by H202 in H9c2 cells, as determined by an MTT assay or microscopy. We also observed that p53 expression was increased by adriamycin, and this increase was not affected by the inhibition of caspase activity, suggesting a role for p53 in adriamycin-induced caspase-independent apoptosis in cardiac toxicity.
 ...
PMID:Induction of caspase-independent apoptosis in H9c2 cardiomyocytes by adriamycin treatment. 1579 49

Many current cancer treatments, including certain classes of chemotherapeutics and radiation, induce cytotoxicity by damaging DNA. However, many cancers are resistant to these therapies, which represents a significant challenge in the clinic. Thus, modulating DNA-damage responses to selectively enhance the sensitivity of cancer cells to these therapies is highly desirable. When DNA damage is detected, DNA checkpoint mechanisms are activated to halt cells at various phases of the cell cycle. Simultaneously, DNA-damage sensors transduce signals to activate DNA-repair mechanisms via de novo expression or post-translational modification of enzymes required for DNA repair. p53 is the major player in a checkpoint that arrests cells at the G1/S boundary, while checkpoint kinase (Chk)1 is critical for the G2/M checkpoint and also the S checkpoint that prevents cell cycle progression after replication defects (intra-S-phase checkpoint) or S/M uncoupling (S/M checkpoint). Poly(ADP-ribose) polymerase is involved in sensing DNA single-strand breaks and inducing DNA repair via poly(ADP-ribosyl)ating various DNA-binding and DNA-repair proteins. In this review, strategies for implementing small-molecule inhibitors of poly(ADP-ribose) polymerase and Chk1, which are emerging as potential adjuncts to current therapies, are discussed.
 ...
PMID:New opportunities in chemosensitization and radiosensitization: modulating the DNA-damage response. 1587 29

Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
 ...
PMID:Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. 1602 17

The p53 binding protein 2 (53BP2) has been identified independently as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). It was demonstrated that over-expression of 53BP2 (renamed as 53BP2S) induces apoptotic cell death. In this study we explored the effect of NF-kappaB activation elicited by a physiological NF-kappaB inducer, interleukin-1beta (IL-1beta), and anti-apoptotic Bcl-2 family proteins on the 53BP2S-mediated apoptosis. We found that both NF-kappaB activation and Bcl-2 family proteins could prevent the 53BP2S-mediated depression of mitochondrial transmembrane potential, activation of caspase-9, cleavage of poly ADP ribose polymerase (PARP), and cell death. These observations suggested that 53BP2S/Bbp and its directly or indirectly interacting proteins might play crucial roles in the regulation of apoptosis and contribute to carcinogenesis. It is also suggested that 53BP2S/Bbp induces apoptosis through the mitochondrial death pathway presumably by counteracting the actions of anti-apoptotic Bcl-2 family proteins. The regulatory network of the 53BP2S-mediated apoptosis cascade including its interacting proteins is discussed.
 ...
PMID:Inhibition of the 53BP2S-mediated apoptosis by nuclear factor kappaB and Bcl-2 family proteins. 1609 44

Knocking out of Nurr1 gene, a member of nuclear receptor superfamily, causes selective agenesis of dopaminergic neurons in midbrain. Reduced expression of Nurr1 increases the vulnerability of mesencephalic dopamine neurons to dopaminergic toxins. We evaluated the role of nitric oxide as a possible mechanism for this increased susceptibility. Increased expression of neuronal nitric oxide synthase and increased 3-nitrotyrosine were observed in striatum of Nurr1 heterozygous (Nurr1 +/-) mice as compared with wild-type. Increased cytochrome C activation and consecutive release of Smac/DIABLO were also observed in Nurr1 +/- mice. An induction of active Caspase-3 and p53, cleavage of poly-ADP (RNase) polymerase and reduced expression of bcl-2 were observed in Nurr1 +/- mice. Methamphetamine significantly increased these markers in Nurr1 +/- mice as compared with wild-type. The present data therefore suggest that nitric oxide plays a role as a modulating factor for the increased susceptibility, but not the potentiation, of the dopaminergic terminals in Nurr1 +/- mice. We also report that this increased neuronal nitric oxide synthase expression and increased nitration in Nurr1 +/- mice led to the activation of apoptotic cascade via the differential alterations in the DNA binding activity of transcription factors responsible for the propagation of growth arrest as well as apoptosis.
 ...
PMID:Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice. 1612 11

Overexpression of EGF receptors and constitutive cyclin D1 expression are frequently associated with human squamous carcinomas. We have now investigated whether these parameters influence susceptibility to okadaic acid induced cell death in EGF-receptor overexpressing mutant p53 A431 human carcinoma. Exposure of these cells to 20 nM okadaic acid induced apoptosis-associated caspase 3 activation, DNA fragmentation, cleavage of Poly ADP-Ribose Polymerase (PARP), p53-independent expression of pro-apoptotic bax, and loss of proliferation-promoting cyclin D1. All these alterations were antagonized by concurrent addition of exogenous EGF. Ectopic overexpression of the cyclin D1 gene in A431 carcinoma conferred resistance to 20 nM okadaic acid irrespective of exogenous EGF, associated with a parallel induction of anti-apoptotic bcl-2. Treatment with a subtoxic concentration of a bispecific bcl-2/bcl xL antisense oligonucleotide cooperated with okadaic acid to down-regulate bcl-2 and sensitize cyclin D1-overexpressing cells to okadaic acid. Although EGF protects EGF-R proficient epithelial cells from diverse apoptotic stimuli through Mcl-1, this is the first report demonstrating that cyclin D1 overexpression provides an EGF independent protection from okadaic acid-induced cell death through induction of bcl-2. We also show that this anti-apoptotic effect of cyclin D1 overexpression, can be partly antagonized with antisense strategies that down-regulate anti-apoptotic bcl-2 family members.
 ...
PMID:Cyclin D1 overexpression induces epidermal growth factor-independent resistance to apoptosis linked to BCL-2 in human A431 carcinoma. 1637 52

PARP-1 interacts with and poly(ADP-ribosyl)ates p53 and topoisomerase I, which both participate in DNA recombination. Previously, we showed that PARP-1 downregulates homology-directed double-strand break (DSB) repair. We also discovered that, despite the well-established role of p53 as a global suppressor of error-prone recombination, p53 enhances homologous recombination (HR) at the RARalpha breakpoint cluster region (bcr) comprising topoisomerase I recognition sites. Using an SV40-based assay and isogenic cell lines differing in the p53 and PARP-1 status we demonstrate that PARP-1 counteracts HR enhancement by p53, although DNA replication was largely unaffected. When the same DNA element was integrated in an episomal recombination plasmid, both p53 and PARP-1 exerted anti-recombinogenic rather than stimulatory activities. Strikingly, with DNA substrates integrated into cellular chromosomes, enhancement of HR by p53 and antagonistic PARP-1 action was seen, very similar to the HR of viral minichromosomes. siRNA-mediated knockdown revealed the essential role of topoisomerase I in this regulatory mechanism. However, after I-SceI-meganuclease-mediated cleavage of the chromosomally integrated substrate, no topoisomerase I-dependent effects by p53 and PARP-1 were observed. Our data further indicate that PARP-1, probably through topoisomerase I interactions rather than poly(ADP-ribosyl)ation, prevents p53 from stimulating spontaneous HR on chromosomes via topoisomerase I activity.
 ...
PMID:Poly(ADP-RIBOSE) polymerase-1 (Parp-1) antagonizes topoisomerase I-dependent recombination stimulation by P53. 1647 54


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