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)

It has been reported that the hexavalent chromium compound (Cr(VI)) can induce both p53-dependent and p53-independent apoptosis. While a considerable amount of information is available on the p53-dependent pathway, only little is known about the p53-independent pathway. To elucidate the p53-independent mechanism, the roles of the Ca(2+)-calpain- and mitochondria-caspase-dependent pathways in apoptosis induced by Cr(VI) were investigated. When human lymphoma U937 cells, p53 mutated cells, were treated with 20 microM Cr(VI) for 24 h, nuclear morphological changes and DNA fragmentation were observed. Production of hydroxyl radicals revealed by electron paramagnetic resonance (EPR)-spin trapping, and increase of intracellular calcium ion concentration monitored by digital imaging were also observed in Cr(VI)-treated cells. An intracellular Ca(2+) chelator, BAPTA-AM, and calpain inhibitors suppressed the Cr(VI)-induced DNA fragmentation. The number of cells showing low mitochondrial membrane potential (MMP), high level of superoxide anion radicals (O(2)(-)), and high activity of caspase-3, which are indicators of mitochondria-caspase-dependent pathway, increased significantly in Cr(VI)-treated cells. An antioxidant, N-acetyl-l-cysteine (NAC), decreased DNA fragmentation and inhibited the changes in MMP, O(2)(-) formation, and activation of caspase-3 induced by Cr(VI). No increase of the expressions of Fas and phosphorylated JNK was observed after Cr(VI) treatment. Cell cycle analysis revealed that the fraction of G2/M phase tended to increase after 24 h of treatment, suggesting that Cr(VI)-induced apoptosis is related to the G2 block. These results indicate that Ca(2+)-calpain- and mitochondria-caspase-dependent pathways play significant roles in the Cr(VI)-induced apoptosis via the G2 block, which are independent of JNK and Fas activation. The inhibition of apoptosis and all its signal transductions by NAC suggests that intracellular reactive oxygen species (ROS) are important for both pathways in Cr(VI)-induced apoptosis of U937 cell.
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PMID:Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells. 1516 45

Neuronal and glial cell death and traumatic axonal injury contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head-injured humans and following experimental brain injury, dying neural cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and necrotic neurons have been identified within contusions in the acute post-traumatic period, and in regions remote from the site of impact in the days and weeks after trauma, while degenerating oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review and compare the regional and temporal patterns of apoptotic and necrotic cell death following TBI and the possible mechanisms underlying trauma-induced cell death. While excitatory amino acids, increases in intracellular calcium and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro- and anti-apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on cellular expression of survival promoting-proteins such as Bcl-2, Bcl-xL, and extracellular signal-regulated kinases, and death-inducing proteins such as Bax, c-Jun N-terminal kinase, tumor-suppressor gene, p53, and the calpain and caspase families of proteases are reviewed. In light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain. Together, these observations suggest that cell death mechanisms may be representative of a continuum between apoptotic and necrotic pathways.
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PMID:Cell death mechanisms following traumatic brain injury. 1519 35

Previous reports have demonstrated that cadmium (Cd) may induce cell death via apoptosis, but the mechanism responsible for cellular death is not clear. In this study, we investigated the signaling pathways implicated in Cd-induced apoptosis in lung epithelial fibroblast (WI 38) cells. Apoptotic features were observed using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, propidium iodide staining and DNA laddering. A treatment of cadmium caused the caspase-8-dependent Bid cleavage, the release of cytochrome c (Cyt c), activation of caspase-9 and -3, and PARP cleavage. A caspase-8 specific inhibitor prevented the Bid cleavage, caspase-3 activation and cell death. Alternatively, we observed that full-length Bax was cleaved into 18-kDa fragment (p18/Bax); this was initiated after 12 h and by 36 h the full-length Bax protein was totally cleaved to the p18/Bax, which caused a drastic release of Cyt c from mitochondria. The p18/Bax was detected exclusively in the mitochondrial fraction, and it originated from mitochondrial full-length Bax, but not from the cytosol full-length Bax. Cd also induced the activation of the mitochondrial 30-kDa small subunit of calpain that was preceded by Bax cleavage. Cd induced the upregulation of Bcl-2 and the degradation of p53 protein. N-acetyl cysteine effectively inhibited the Cd-induced DeltaPsim reduction, indicating ROS acts upstream of mitochondrial membrane depolarization. Taken together, our results suggest that Cd-induced apoptosis was thought to be mediated at least two pathways; caspase-dependent Bid cleavage, and the other is calpain-mediated mitochondrial Bax cleavage. Moreover, we found that the function of Bid and Bax was not dependent of Bcl-2, and that ROS can also contribute in the Cd-induced cell death.
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PMID:Cadmium induces apoptotic cell death in WI 38 cells via caspase-dependent Bid cleavage and calpain-mediated mitochondrial Bax cleavage by Bcl-2-independent pathway. 1545 Sep 50

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family that is mostly seen in neurons, does not vary with cell cycle, and is activated in many neurodegenerative disorders and other non-neuronal pathologies, but its relationship to non-neuronal apoptosis is not understood, nor is the control of the activation of Cdk5 by its activators. The most widely studied activator of Cdk5, p35, is cleaved to p25 by calpain, an event that has been linked with activation of Cdk5 and neuronal death. Here we report that calpain-mediated Cdk5/p25 activation accompanies non-neuronal as well as neuronal cell death, suggesting that the p35/calpain/p25/Cdk5 activation sequence is a general feature of cell death. We further demonstrate that Cdk5 can be activated in the absence of p53, Apaf-1, caspase-9, and -3 during cell death, indicating that its activation relates more to cell death than to a specific pathway of apoptosis.
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PMID:p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death. 1602 Nov 78

The E2F1 transcription factor can initiate proliferation or apoptosis, the latter by both transcription-dependent and -independent mechanisms. Recently, an E2F1 mutant lacking the DNA binding domain, E2F1(180-437), has been implicated in degradation of MDMX and MDM2 proteins via lysosomal proteases. MDM proteins block p53 dependent apoptosis by directly inhibiting p53 stability and function. Here we demonstrate E2F1(180-437) induces death in HEK293 cells independent of E2F1 transcriptional activation and p53 stabilization. E2F1(180-437) elevates the activity of the calcium-activated protease, calpain, which is required for E2F1 induced proteolysis of MDMX and E2F1 induced cell loss. To determine if E2F1 could be activating proteolysis via calpains in neurodegeneration, we examined MDMX immunofluorescence in simian immunodeficiency virus encephalitis (SIVE). We found a reciprocal relationship between E2F1 and MDMX staining: in SIVE where E2F1 immunostaining is increased, MDMX is decreased, while in controls where E2F1 immunostaining is low, MDMX is high. Together these experiments support a new function for E2F1 in the activation of calpain proteases and suggest a role for this pathway in SIVE.
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PMID:E2F1 induces cell death, calpain activation, and MDMX degradation in a transcription independent manner implicating a novel role for E2F1 in neuronal loss in SIV encephalitis. 1608 44

Juglone (5-hydroxy-1,4-naphtoquinone) is a natural toxin produced by walnut trees. In this study we show that juglone differentially reduces viability of human cells in culture. Normal fibroblast were found to be especially sensitive to juglone and lost viability primarily through a rapid apoptotic and necrotic response. This response may have been triggered by DNA damage since juglone induced a rapid and strong phosphorylation of H2AX in all phases of the cell cycle. Furthermore, juglone inhibits mRNA synthesis in human fibroblasts in a dose-dependent manner. Surprisingly, juglone caused a drastic reduction of the basal level of p53 in human fibroblasts and this loss could not be fully rescued by proteasome and calpain I inhibitors. However, when cells were pretreated with UV light or ionizing radiation, juglone was not able to reduce the cellular levels of activated p53. Our results show that juglone has multiple effects on cells such as the induction of DNA damage, inhibition of transcription, reduction of p53 protein levels and the induction of cell death.
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PMID:The natural toxin juglone causes degradation of p53 and induces rapid H2AX phosphorylation and cell death in human fibroblasts. 1627 20

Status epilepticus (SE)-induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic N-methyl-D-aspartate (NMDA) receptors and triggers receptor-mediated calcium influx (excitotoxicity). This results in activation of intracellular proteases and neuronal nitric oxide synthase, with generation of free radicals, and damage to cellular membranes, structural proteins, and essential enzymes. Programmed cell death mechanisms, such as p53 activation, activation of cell death-promoting Bcl-2 family members, and endonuclease-induced DNA laddering, occur in SE-induced neuronal death. Caspase-independent excitotoxic mechanisms, such as NMDA-induced calpain I activation, with activation and translocation of the cell death-promoting Bcl-2 family member Bid from cytoplasm to mitochondria, and subsequent translocation of apoptosis-inducing factor and endonuclease G to nuclei (which cause large-scale and internucleosomal DNA cleavage, respectively), may be triggered by SE. Poly(ADP-ribose) polymerase-1 (PARP-1) activation and cysteinyl cathepsin and DNase II release from lysosomes may occur following SE as well, but these events await future investigation. In the future, rational combinations of central nervous system-penetrable neuroprotective agents, based on our knowledge of excitotoxic mechanisms, may be useful in refractory human SE.
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PMID:Prolonged seizures and cellular injury: understanding the connection. 1627 99

Overexpression of cyclin E in breast tumors is associated with a poor response to tamoxifen therapy, greater genomic instability, more aggressive behavior, and a poor clinical prognosis. These tumors also express low molecular weight isoforms of cyclin E that are associated with higher kinase activity and increased metastatic potential. In the current study, we show that cyclin E overexpression in MCF7 cells transactivates the expression of calpain 2, leading to proteolysis of cyclin E as well as several known calpain substrates including focal adhesion kinase (FAK), calpastatin, pp60src, and p53. In vivo inhibition of calpain activity in MCF7-cyclin E cells impedes cyclin E proteolysis, whereas in vivo induction of calpain activity promotes cyclin E proteolysis. An analysis of human breast tumors shows that high levels of cyclin E are coincident with the expression of the low molecular weight isoforms, high levels of calpain 2 protein, and proteolysis of FAK. Lastly, studies using a mouse model of metastasis reveal that highly metastatic tumors express proteolyzed cyclin E and FAK when compared to tumors with a low metastatic potential. Our results suggest that cyclin E-dependent deregulation of calpain may be pivotal in modifying multiple cellular processes that are instrumental in the etiology and progression of breast cancer.
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PMID:Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype. 1632 14

Apoptotic loss of CD4+ T cells has been proposed as a mechanism of T cell depletion in human immunodeficiency virus (HIV) infections resulting in immunodeficiency. The Env glycoprotein has been implicated in apoptosis of uninfected bystander cells via gp120 binding to CD4/CXC chemokine receptor 4 as well as the fusion/hemifusion process mediated by gp41. Using an in vitro model of coculture of Env-expressing cells as effectors and CD4+ T cells as targets, we find that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41-induced hemifusion. Further, the apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production. HIV gp41-induced mitochondrial depolarization is inhibited by protease inhibitor nelfinavir but not by other HIV protease inhibitors or inhibitors of calpain and cathepsin. This "kiss of death" (hemifusion) signaling pathway is independent of p38 mitogen-activated protein kinase and p53, making it distinct from the apoptosis seen in syncytia. We also show that virion-induced apoptosis is gp41-dependent. Our findings provide new insights into the mechanism via which HIV gp41 mediates apoptosis in bystander cells.
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PMID:HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir. 1633 May 30

Calcineurin (CaN), a Ca2+-calmodulin (CaM)-dependent protein phosphatase, is important for Ca2+-mediated signal transduction. The main objective of this study was to examine the potential role of CaN in epileptic brain and its involvement in neuronal apoptosis. We investigated CaN expression and its interaction with various signaling molecules in normal, carrier and epileptic brain tissues of chicken. Our results revealed higher Ca2+-CaM-dependent phosphatase activity of CaN and a correspondingly strong immunoreactive band of CaN A in epileptic and carrier brain samples compared with normal brain. Furthermore, immunohistochemical analysis showed a higher level of expression of CaN in epileptic brain tissue. However, the intensity of immunoreactivity was less in carrier than epileptic brain. We observed that the interaction of CaN with m-calpain and micro-calpain was strong in carrier and epileptic chickens compared with that in normal birds. In addition, the interaction of CaN with Bcl-2, caspase-3 and p53 was greater in carrier and epileptic fowl than in normal chickens. The greater interaction of CaN with various apoptotic factors in epileptic chickens adds to our understanding of the mechanism of CaN signaling in neuronal apoptosis.
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PMID:Expression of calcineurin and its interacting proteins in epileptic fowl. 1633 33


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