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)

Anticancer drugs can induce tumour cell death by apoptosis. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondria. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumour cells to their cognate ligands, which could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, which includes anti- and pro-apoptotic molecules, regulates cell sensitivity at the mitochondrial level. Chemotherapeutic drugs modulate their expression (e.g. through p53-dependent gene transcription), their activity (e.g. by phosphorylation) and their subcellular localization (e.g. by translocation of pro-apoptotic proteins from the cytosol to the mitochondria). When interacting with tumour cells, anticancer drugs also activate lipid- and kinase-dependent signalling pathways that modulate the death response to specific damage. Protective pathways include activation of NF kappa B transcription factor, accumulation of heat shock proteins and activation of proteins involved in cell cycle regulation. The recent identification on these pathways to cell death has suggested several new strategies to improve the therapeutic efficacy of currently used anticancer drug regimens.
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PMID:Modulation of apoptotic pathways triggered by cytotoxic agents. 1180 87

Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.
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PMID:Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases. 1181 Jan 83

The mechanisms of injury-induced apoptosis of neurons within the spinal cord are not understood. We used a model of peripheral nerve-spinal cord injury in the rat and mouse to induce motor neuron degeneration. In this animal model, unilateral avulsion of the sciatic nerve causes apoptosis of motor neurons. We tested the hypothesis that p53 and Bax regulate this neuronal apoptosis, and that DNA damage is an early upstream signal. Adult mice and rats received unilateral avulsions causing lumbar motor neurons to achieve endstage apoptosis at 7-14 days postlesion. This motor neuron apoptosis is blocked in bax(-/-) and p53(-/-) mice. Single-cell gel electrophoresis (comet assay), immunocytochemistry, and quantitative immunogold electron microscopy were used to measure molecular changes in motor neurons during the progression of apoptosis. Injured motor neurons accumulate single-strand breaks in DNA by 5 days. p53 accumulates in nuclei of motor neurons destined to undergo apoptosis. p53 is functionally activated by 4-5 days postlesion, as revealed by immunodetection of phosphorylated p53. Preapoptotically, Bax translocates to mitochondria, cytochrome c accumulates in the cytoplasm, and caspase-3 is activated. These results demonstrate that motor neuron apoptosis in the adult spinal cord is controlled by upstream mechanisms involving DNA damage and activation of p53 and downstream mechanisms involving upregulated Bax and cytochrome c and their translocation, accumulation of mitochondria, and activation of caspase-3. We conclude that adult motor neuron death after nerve avulsion is DNA damage-induced, p53- and Bax-dependent apoptosis.
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PMID:Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent. 1181 Jun 34

The role of the hepatitis B virus protein HBx in liver cell proliferation and apoptosis remains controversial. Using a transgenic mouse model, we have recently shown that HBx stimulates the apoptotic turnover of hepatocytes, independently of p53. In this paper, we tested whether the proapoptotic function of HBx can interfere with Bcl-2 during hepatic apoptosis in vivo. HBx transgenic mice were crossed with PK-hBcl-2 mice that are protected against Fas killing by constitutive overexpression of Bcl-2 in hepatocytes. In a lethal challenge with Fas antibodies, HBx expressed at low levels restored sensitivity to Fas-mediated apoptosis and fulminant hepatic failure in mice overexpressing Bcl-2. Furthermore, cytochrome c release from mitochondria and caspase 3 activation were restored to normal levels in HBx/Bcl-2 mice during transduction of the Fas signal. Thus, the proapoptotic activity of HBx overcomes or bypasses the inhibitory effect of Bcl-2 against Fas cytotoxicity. This effect was not apparently mediated through downregulation of the PK-hBcl-2 transgene or via delocalization of the Bcl-2 protein, and a direct interaction of HBx with Bcl-2, Bcl-X(L) or Bax could not be evidenced in yeast two-hybrid assays. We further show that apoptosis induced by ectopic expression of HBx is associated with mitochondrial membrane alterations and caspase 3 activation. Our data indicate that the dominant function of HBx upon Bcl-2-regulated control of apoptosis might play an important role in the pathogenesis of chronic hepatitis B.
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PMID:The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver. 1182 50

Increasing evidence provides support for oxidative stress to be closely linked to apoptosis. Reactive oxygen species (ROS) are thought to be involved in many forms of programmed cell death. Though heat shock is a universal phenomenon, BC-8, a macrophage-like cell line failed to mount a typical heat shock response. In the absence of heat shock proteins and functional p53, BC-8 cells undergo apoptosis through CD95 signaling. In the present study, we have investigated the role of ROS in the regulation of apoptosis in these cells. We show that cells transfected with hsp70 and functional p53 are resistant to heat-induced apoptosis through inhibition of CD95 expression and ROS induction. Furthermore, apoptosis in BC-8 cells resulted in two bursts of ROS generation, one correlated with heat stress and intracellular depletion of GSH and the other with Bax overexpression and cytochrome c release. Antioxidants could not protect these cells from heat-induced apoptosis and the death pathway seems to be dependent on initial signaling cascade subsequently altering the intracellular redox. Hence, our data suggest that ROS generation in BC-8 cells upon heat shock is facultative but not obligatory for apoptosis.
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PMID:A cross talk between cellular signalling and cellular redox state during heat-induced apoptosis in a rat histiocytoma. 1182 47

The mechanisms of cytoprotection conferred by stress preconditioning remain largely uncharacterized in endothelial cells (EC). We report that stress preconditioning of EC with serum starvation induces the release of soluble mediator(s) that confer resistance to apoptosis, increase proliferation, and enhance angiogenesis in a second set of "non-preconditioned" EC. Preconditioning was found to target specifically the mitochondrial control of apoptosis in EC with increased protein levels of Bcl-2, decreased protein levels of Bax, and decreased cytosolic release of cytochrome c. Regulators of apoptosis acting upstream and downstream of the mitochondria such as p53, cIAP-1, cIAP-2, and XIAP were not altered. Mediators classically associated with preconditioning in other cell types such as adenosine, opioids, and nitric oxide are not implicated in this cytoprotective loop. Blockade of protein kinase C-dependent signaling inhibited cytoprotection of EC. Further characterization of this paracrine pathway should provide insights into the molecular regulation of preconditioning in endothelial cells.
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PMID:Paracrine repercussions of preconditioning on angiogenesis and apoptosis of endothelial cells. 1184 99

Apoptotic processes have been associated with cancer and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease etc. beta-Alanyl-L-histidine (L-carnosine), occurring abundantly in skeletal muscles has been suggested to possess antioxidative activity. We investigated whether L-carnosine prevents 12-O-tetradecanoylphorbol-13-acetate (TPA)- or hydrogen peroxide (H2O2)-induced apoptosis involving mitochondria in the v-myc transformed rat liver epithelial cells (WB-myc cells). L-Carnosine prevented both TPA- and H2O2-induced DNA fragmentation, the loss of mitochondrial membrane potentials and blocked the release of cytochrome c into cytosol. Subsequently, the cleavages of poly (ADP-ribose) polymerase were significantly reduced in L-carnosine-treated cells. However, western blotting analysis revealed that p53 protein level did not change for 12h after TPA- and H2O2-treatment. Therefore, these results suggested that L-carnosine, an antioxidant, protected both H2O2- and TPA-induced apoptosis through mitochondrial pathways.
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PMID:Protective effect of L-carnosine against 12-O-tetradecanoylphorbol-13-acetate- or hydrogen peroxide-induced apoptosis on v-myc transformed rat liver epithelial cells. 1184 41

The p53 tumor suppressor protein inhibits tumor formation, in part by inducing apoptosis, which is inhibited by anti-apoptotic Bcl-2 family members Bcl-2 and adenovirus E1B 19K. We have identified p53-apoptotic signaling events which are targeted for inhibition by E1B 19K. Apoptotic signaling by p53 induced a Bid-independent conformational change in Bax, a Bax-Bak interaction, release of cytochrome c and Smac/DIABLO from mitochondria, caspase-9 and -3 activation, cleavage of known caspase substrates, and apoptosis. When p53-dependent apoptosis was blocked by E1B 19K expression, E1B 19K bound Bak, and the Bax-Bak interaction was inhibited. Cytochrome c and Smac/DIABLO release from mitochondria was also inhibited in E1B 19K expressing cells and cells remained viable. After a prolonged p53 death stimulus, the inhibition of the mitochondrial death checkpoint by E1B 19K failed, and cytochrome c and Smac/DIABLO were released from mitochondria, and became degraded. Despite this eventual failure to inhibit the mitochondrial checkpoint, caspase-9 and -3 were not activated, and cells remained viable even upon treatment with an exogenous death stimulus. Thus, p53 induces apoptosis in part through Bax and Bak, and even an incomplete inhibition of this mitochondrial checkpoint may be sufficient to confer resistance to cell death.
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PMID:Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. 1185 Aug 3

The mechanism of bFGF-induced cell death in tumours of the Ewing's sarcoma family (ESFT) has been investigated. bFGF-induces phosphorylation of FGFr 1 and activation of Ras/ERK in ESFT cells that die when exposed to bFGF. Induction of cell death was associated with activation of both initiator (caspases-2, -8 and -10) and effector (caspases-3, -6 and -7) caspases. Moreover, the general caspase inhibitor Z-VAD-FMK protected cells from bFGF-induced cell death. After treatment with bFGF, a loss of mitochondrial transmembrane potential was accompanied by down-regulation of Bcl-2. However, the observed cell death was not associated with release of cytochrome c from the mitochondria. Furthermore, expression of wild-type p53 was not required for bFGF-induced cell death. These observations suggest that bFGF-induced cell death may be mediated through a cell death receptor mechanism, supported by up-regulation of the p75 neurotrophin receptor. bFGF-induced cell death was associated with up-regulation of p21 and p53, down-regulation of PCNA and cyclin A and a decrease in active pRb1, changes consistent with accumulation of cells in G1. These data demonstrate that bFGF-induced cell death is effected through a caspase-dependent and p53-independent mechanism, that may be mediated through a cell death receptor pathway.
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PMID:Basic fibroblast growth factor (bFGF)-induced cell death is mediated through a caspase-dependent and p53-independent cell death receptor pathway. 1185 Aug 9

In our study, we show that expression of HPV-16 E6 sensitizes TNF-induced cytotoxicity of human ovarian cancer cell line A2780. This effect is not related to a different number of TNF receptors present on cell membrane. The major induction of massive apoptosis induced by TNF is not p53- and p21(waf-1)-dependent but it is principally related to NF-kappaB inhibition in A2780/E6 cells. Consistently to NF-kappaB inhibition a rapidly release of cytochrome c and severe induction of DNA fragmentation are seen in A2780/E6 cells. Also in human colon cancer cell line HCT-116/E6 the expression of HPV-16 E6 enhances TNF-cytotoxicity. This effect is not present in the HCT-116/mu-p53 clone (transfected with a dominant-negative mutated p53 transgene). Thus, taken together all these observations suggest that HPV-16 E6 sensitizes A2780 and HCT-116 cells to TNF; this effect is not p53-dependent, but it is essentially mediated through an inhibition in activating NF-kappaB activities.
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PMID:Human papillomavirus type 16 E6-enhanced susceptibility to apoptosis induced by TNF in A2780 human ovarian cancer cell line. 1185 47


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