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)

Severe uteroplacental insufficiency causes cerebral apoptosis in the fetus. Moderate uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and increases the risk of postnatal neurological morbidity. In the rat, uteroplacental insufficiency and IUGR affect cerebral gene expression of Bcl-2 and predispose the newborn IUGR rat toward cerebral apoptosis when challenged with perinatal hypoxia. Expression of Bcl-2, as well as the proapoptotic protein Bax, is regulated by p53. p53 also induces MDM2 transcription, which functions to limit further p53-induced apoptosis. The predisposition of the IUGR fetus toward cerebral apoptosis suggests that the p53-MDM2 "functional" circuit may be perturbed in the newborn IUGR rat brain. We hypothesized that MDM2 cerebral expression does not increase in response to increased p53 expression or increased levels of phospho-p53 (Ser15), an activated form of p53. To prove this hypothesis, we induced IUGR through bilateral uterine ligation of the pregnant rat. Uteroplacental insufficiency significantly increased p53 mRNA, total p53 protein, and phospho-p53 (Ser15) protein levels in the brain at term. Increased expression of phospho-p53 (Ser15) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were localized to the CA1 region of the hippocampus, the subcortical and periventricular white matter, and the amygdala of the IUGR rat brain. In contrast, uteroplacental insufficiency decreased cerebral MDM2 mRNA and phospho-MDM2 (Ser166) protein levels in the IUGR rat pups. We conclude that the cerebral MDM2 response to increased p53 expression is not present in the newborn IUGR rat pup, and we speculate that this contributes to the predisposition of the IUGR fetus toward perinatal and long-term neurodevelopmental morbidities.
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PMID:Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency. 1556 74

Cyclin G1 (CG1) was identified as a p53-transactivated target gene, and yet its physiological and pathological roles have been unclear. Here, we demonstrate that CG1 is translocated from cytoplasm to the nuclei of neurons in response to variety of injuries. In the normal matured rodent brain, CG1 immunoreactivity was hardly observed; however, some brain injuries exhibited intense CG1 immunoreactivity in the nuclei of the damaged neurons. Transient common carotid artery occlusion (CCAO) in the gerbil showed strong CG1-like immunoreactivity in the hippocampal CA1 neurons, and permanent middle cerebral artery occlusion (MCAO) in the mouse showed strong CG1-like immunoreactivity in the nuclei of neurons located in the ischemic brain regions. TUNEL staining did not exactly overlap with the CG1-positive cells, but overlapped highly with Fluoro-Jade B staining, a degeneration marker. Brain trauma caused by knife cut, cold injury, and kinate injection also showed CG1 accumulation in the neuronal nuclei located near the injury site. These observations were obtained in p53-deficient mice as well, suggesting that the accumulation of CG1 in the injured neurons is p53-independent. A similar nuclear translocation of endogenous CG1 was confirmed in a primary culture of cortical neurons when a toxic level of N-methyl-D-aspartate (NMDA) was applied. These results demonstrate that nuclear translocation of CG1 from cytoplasmic region occurs in damaged and degenerating neurons in a p53-independent manner, and the CG1 nuclear staining could be a good marker for the neurons received fatal damages.
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PMID:The p53-independent nuclear translocation of cyclin G1 in degenerating neurons by ischemic and traumatic insults. 1586 37

Our previous data indicate that ischemia and amyloid beta peptide (A beta) cause an oxidative damage to macromolecules. In the present study we investigated the role of p53 protein in cell survival and death after administration of A beta. The experiments were carried out on pheochromocytoma cells (PC-12) and cortical primary neurons in culture. The cortical neurons were exposed (48 h, 10 microM) to the action of a short A beta 25-35 neurotoxic fragment and the involvement of p53 was evaluated after addition of the p53 inhibitor pifithrin-alpha. Changes in cell morphology were evaluated by 4', 6-diamidino-2-phenylindole staining and the concentration-dependent effect of pifithrin-alpha on cells viability was determined. Additionally, we studied the effect of pifithrin-alpha on neuronal survival in vivo after a 5-min global brain ischemia followed by 7 days' reperfusion in gerbils. We found that A beta enhanced apoptotic cell death in cortical primary neurons. Pifithrin-alpha, at a 10 microM final concentration, protected the neuronal cells from the apoptotic death. However, at concentrations of 0.1 and 1 mM, the p53 inhibitor decreased PC-12 cells' viability in a dose-dependent manner. In in vivo experiments we did not observe any neuroprotection by pifithrin-alpha in the CA1 hippocampal layer, which suggests that its effects strongly depend on the duration and type of an ischemic insult. Our data indicate that pifithrin-alpha affects neuronal cells in a dual manner. It has a protective effect at a low concentration, but becomes neurotoxic at higher concentrations.
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PMID:Effects of p53 inhibitor on survival and death of cells subjected to oxidative stress. 1620 96

DNA repair plays a critical, but imprecisely defined role in excitotoxic injury and neuronal survival throughout adulthood. We utilized an excitotoxic injury model to compare the location and phenotype of degenerating neurons in mice (strain 129-C57BL) deficient in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), an enzyme required for nonhomologous end joining (NHEJ). Brains from untreated adult heterozygous and DNA-PKcs null mice displayed comparable cytoarchitecture and undetectable levels of cell death. By day 1, and extending through 4 days following kainic acid-induced seizures, brains from DNA-PKcs null mice showed widespread neurodegeneration that encompassed the entire hippocampal CA1-CA3 pyramidal cell layer, entorhinal cortex, and lateral septum, with relative sparing of the dentate gyrus granule cell layer and hilus, as judged by toluidine blue, Fluoro-Jade B, and terminal dUTP nick end labeling staining. In contrast, seizure-related neurodegeneration in heterozygous littermates was limited to the CA3 region of the hippocampus. NeuN and calbindin staining revealed a selective decrease in the number and density of NeuN-positive neurons in the pyramidal layers of degenerating regions in both heterozygous and DNA-PKcs null mice. To elucidate the mechanisms leading to cell death, we examined an involvement of the p53 pathway, known to be induced by DNA damage. Addition of pifithrin-alpha, a p53 inhibitor, or expression of a dominant-negative p53 rescued neurons from kainate-induced excitotoxic cell death in primary cortical cultures derived from wildtype, DNA-PKcs heterozygous, or DNA-PKcs null neonatal mice. Moreover, pifithrin-alpha prevented kainate-induced loss of mitochondrial membrane potential, dendrite degeneration, and cell death. Results suggest that NHEJ plays a neuroprotective role in excitotoxicity, within the perforant, Schaffer collateral, hippocampal-septal, and temperoammonic pathways, in part by repairing DNA damage that would otherwise result in activation of a p53-dependent apoptotic cascade.
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PMID:DNA damage and nonhomologous end joining in excitotoxicity: neuroprotective role of DNA-PKcs in kainic acid-induced seizures. 1621 17

Oxygen-sensing and responses to changes in oxygen concentration is a fundamental property of cellular physiology. In the central nervous system (CNS), hippocampal CA1 neurons are known to be extremely vulnerable to low oxygen concentrations or anoxia. Understanding the mechanisms governing tolerance to oxygen depletion is vital for developing strategies to protect the brain from hypoxic-ischemic insult. Our current study demonstrates the protective mechanism of KATP channels on hippocampal CA1 neurons subjected to hypoxic or anoxic conditions. Specifically, we show that CA1 neurons undergo apoptosis when depleted of oxygen for 12 or 24 h. A KATP channels agonist diazoxide inhibits the observed apoptosis. The inhibition of apoptosis is mediated through diazoxide's ability to reduce p53 expression. On the other hand, tolbutamide, a KATP channels antagonist which blocks the cellular sulphonylureas receptor, significantly increases p53 expression and apoptosis under hypoxic/anoxic conditions. Trichostatin (TSA), a p53 inhibitor, can block the effects of tolbutamide, lending further support for a role of p53 in mediating this process. These studies demonstrate that KATP channels act as an upstream antagonist of p53 in hippocampal CA1 neurons, and suggests their protective role in cerebral hypoxia.
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PMID:Activation of ATP-sensitive K channels protects hippocampal CA1 neurons from hypoxia by suppressing p53 expression. 1642 53

Although p53 controls cell death after various stresses, its role in neuronal death after brain ischemia is poorly understood. To address this issue, we subjected p53-deficient (p53-/- and p53+/-) mice (backcrossed for 12 generations with C57BL/6 mice) and wild-type mice (p53+/+) to transient global ischemia by the three-vessel occlusion method. Despite similar severity of ischemia, as shown by anoxic depolarization and cortical blood flow, neuronal death in the hippocampal cornus ammonis (CA)1 region was much more extensive in p53+/+ than in p53-/- mice (surviving neuronal count, 9.3%+/-3.0% versus 61.3%+/-34.0% of nonischemic p53+/+ controls, respectively, P<0.0037). In p53+/- mice, a similar trend was also observed, though not statistically significant (43.5% of nonischemic p53+/+ controls). In p53+/+ mice, p53-like immunoreactivity in hippocampal CA1 neurons was enhanced at 12 h after ischemia, and messenger ribonucleic acid for Bax, a direct downstream target of p53, was also increased. These results indicate that p53 potentiates ischemic neuronal death in vivo and suggest that this molecule could be a therapeutic target in neuronal death after cerebral ischemia.
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PMID:p53 potentiates hippocampal neuronal death caused by global ischemia. 1653 33

Long-term adrenalectomy induces a dramatic loss of cells in the dentate gyrus and CA1-CA4 fields of the hippocampus resulting in an impairment of cognitive functions such as spatial learning, memory and exploratory behaviour. Muscarinic M1 and M4 receptor levels in the hippocampus and entorhinal cortex of adult male Wistar rats were examined 3, 14, 30, 90, and 150 days after adrenalectomy. Receptor levels in the entorhinal cortex and the hippocampus were determined by quantitative autoradiography using 125I-M1-toxin-1 and 125I-M4-toxin-1, M1 and M4 subtype selective antagonists, respectively. Moreover, the level of hippocampal M1 and M4 muscarinic receptors were evaluated 1 month after adrenalectomy by immunoblot analysis. Adrenalectomy induced apoptotic processes were examined by analysing apoptotic markers using Western blot analysis. No significant changes were observed in the level of muscarinic M1 receptors in the entorhinal cortex, the dentate gyrus and in the different CA fields of the hippocampus of adrenalectomized (ADX) rats. However, M4 receptors showed a significant decrease in the entorhinal cortex (at 3 days), dentate gyrus and CA4 (at 14 days), CA3 (at 30 days), and CA2 and CA1 (at 90 days) after adrenalectomy. Moreover, a decrease in the level of M4 receptors was detected in ADX rats 1 month after adrenalectomy as compared with sham groups using M4 specific antibody. Apoptotic markers such as PARP and p53 were significantly increased whereas Bcl-2 marker was decreased in ADX rat brain homogenates compared to controls. Our results show that M1 and M4 receptors are differentially affected by adrenalectomy and indicate that these subtypes have different functions in the hippocampus. Our data on time and region-dependent decreases in hippocampal M4 receptors indicate that the M4 receptor subtype is influenced by adrenal hormones and suggest that the M4 receptor might be linked to memory function in the hippocampus.
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PMID:Temporal and region-dependent changes in muscarinic M4 receptors in the hippocampus and entorhinal cortex of adrenalectomized rats. 1667 64

Although p53 is a key modulator of cellular stress responses, the mechanism of p53-mediated apoptosis is ambiguous. p53 can mediate apoptosis in response to death stimuli by transcriptional activation of proapoptotic genes and transcriptional-independent mechanisms. Recent studies have shown that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming a inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release. However, how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischemia remains unclear. We examined the interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons in rats using a transient global cerebral ischemia (tGCI) model. Western blot analysis and immunofluorescent staining revealed mitochondrial p53 translocation after tGCI in the hippocampal CA1 neurons. Coimmunoprecipitation revealed that translocated p53 bound to Bcl-X(L) in the mitochondrial fraction. To examine the effect of a specific p53 inhibitor on the mitochondrial p53 pathway and apoptotic cell death after tGCI, we intravenously administered pifithrin-alpha (PFT). Mitochondrial p53 translocation and interaction between p53 and Bcl-X(L) were prevented by treatment with PFT. Moreover, cytochrome c release from mitochondria and subsequent apoptotic CA1 neuronal death were decreased with PFT treatment. These results suggest that the mitochondrial p53 pathway is one of the novel mechanisms mediating delayed death of vulnerable hippocampal CA1 neurons after tGCI.
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PMID:Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. 1687 Jul 42

p53, a tumour suppressor, is involved in DNA repair and cell death processes and mediates apoptosis in response to death stimuli by transcriptional activation of pro-apoptotic genes and by transcription-independent mechanisms. In the latter process, p53 induces permeabilization of the outer mitochondrial membrane by forming an inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release in several cell line systems. However, it is unclear how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischaemia. We examined interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons using a tGCI (transient global cerebral ischaemia) rat model. We showed mitochondrial translocation of p53 and its binding to Bcl-X(L). Mitochondrial p53 translocation, interaction between p53 and Bcl-X(L), and cytochrome c release from mitochondria and subsequent CA1 neuronal death were prevented by pifithrin-alpha, a p53-specific inhibitor. These results suggest that the mitochondrial p53 pathway plays a role in delayed CA1 neuronal death after tGCI.
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PMID:Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia. 1707 2

We investigated the immunohistochemical alterations of the transcription nuclear factor kappa-B (NF-kappaB) and transcription factor p53 in the hippocampus after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the alterations of NF-kappaB, p53 and neuronal nuclei in the hippocampus after ischemia. Severe neuronal damage was observed in the hippocampal CA1 neurons 5 and 14 days after ischemia. In the present study, the increase of NF-kappaB immunoreactivity in glial cells and p53 immunoreactivity in neurons preceded neuronal damage in the hippocampal CA1 sector after ischemia. Thereafter, NF-kappaB immunoreactivity was induced highly in reactive astrocytes and microglia of the hippocampal CA1 sector where severe neuronal damage was observed. Our immunohistochemical study showed that pitavastatin prevented the alterations of NF-kappaB and p53 in the hippocampal CA1 sector 5 days after transient ischemia. Furthermore, our results with neuronal nuclei immunostaining indicate that pitavastatin dose-dependently prevented the neuronal cell death in the hippocampal CA1 sector 5 days after transient cerebral ischemia. These results suggest that the up-regulations of NF-kappaB in glia and p53 in neurons can cause neuronal cell death after ischemia. Our findings also support the hypothesis that NF-kappaB- and/or p53-mediated neuronal cell death is prevented through decreasing oxidative stress by pitavastatin. Thus, NF-kappaB and p53 may provide an attractive target for the development of novel therapeutic approaches for brain stroke.
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PMID:Immunohistochemical study on distribution of NF-kappaB and p53 in gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin. 1722 97


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