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)

Initiation of nitric oxide (NO.)-mediated apoptotic cell death in RAW 264.7 macrophages is associated with up-regulation of mitochondrial manganese superoxide dismutase (MnSOD; SOD2) and down-regulation of cytosolic copper zinc superoxide dismutase (CuZnSOD; SOD1) at their individual mRNA and protein levels. To evaluate the decreased CuZnSOD expression and the initiation of apoptosis we stably transfected macrophages to overexpress human CuZnSOD. Individual clones revealed a 2-fold increase in CuZnSOD activity. Expression of a functional and thus protective CuZnSOD was verified by attenuated superoxide (O2(.)-)-mediated apoptotic as well as necrotic cell death. In this study we showed that SOD-overexpressing macrophages (R-SOD1-12) were also protected against NO.-initiated programmed cell death. Protection was substantial towards NO. derived from exogenously added NO donors or when NO. was generated by inducible NO synthase activation, and was evident at the level of p53 accumulation, caspase activation and DNA fragmentation. Stimulation of parent and SOD-overexpressing cells with a combination of lipopolysaccharide and murine interferon gamma produced equivalent amounts of nitrite/nitrate, which ruled out attenuated inducible NO. synthase activity during protection. Because protection by a O2(.)--scavenging system during NO. -intoxication implies a role of NO. and O2(.)- in the progression of cell damage, we used uric acid to delineate the role of peroxynitrite during NO.-elicited apoptosis. The peroxynitrite scavenger uric acid left S-nitrosoglutathione or spermine-NO-elicited apoptosis unaltered, blocking only 3-morpholinosydnonimine-mediated cell death. As a result we exclude peroxynitrite from contributing, to any major extent, to NO. -mediated apoptosis. Therefore protection observed with CuZnSOD overexpression is unlikely to stem from interference with peroxynitrite formation and/or action. Unequivocally, the down-regulation of CuZnSOD is associated with NO. cytotoxicity, whereas CuZnSOD overexpression protects macrophages from apoptosis.
 ...
PMID:Overexpression of CuZn superoxide dismutase protects RAW 264.7 macrophages against nitric oxide cytotoxicity. 1002 4

The activities of antioxidant enzymes, and the expression of p21(WAF1) and p53 proteins were studied at different times after subculture during proliferation and differentiation phases. Two human melanoma cell lines were used: IPC182, which is a non-differentiating cell line, and IGR221, which spontaneously differentiates at the end of the exponential growth phase, as evidenced by a marked increase of melanin content and tyrosinase activity. In the two cell lines, the slowing of proliferation coincided with an increase in the activity and amount of immunoreactive superoxide dismutases (SOD1 and SOD2), and a decrease of catalase and glutathione peroxidase activities, and of the glutathione content. The levels of p21WAF1 and p53 proteins were found to be lower in confluent than in proliferative cells. Several parameters were modified only during the differentiation phase of IGR221 cells; in these cells the increase of tyrosinase activity was highly correlated with the increase in SOD2, GST, glutathione reductase, and G6PD activities. The level of glutathione was found to be lower in differentiated IGR221 than in non-differentiated IPC182 cells. These results suggest that p21WAF1 and p53 proteins are not involved in the spontaneous differentiation process of melanoma cells, and that abnormal regulation of the cell cycle inhibition pathway occurred in these cells. The results sustain the hypothesis that alterations of antioxidant enzyme expression are involved in the control of proliferation and differentiation of melanoma cells. Alterations of SOD2 activity may be of particular importance, since variations are observed with both cell growth and cell differentiation.
 ...
PMID:Modulation of antioxidant enzymes p21WAF1 and p53 expression during proliferation and differentiation of human melanoma cell lines. 1023 48

Familial amyotrophic lateral sclerosis (ALS) has been linked in some families to dominantly inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (Cu-Zn SOD1). Transgenic mice expressing a mutant human Cu-Zn SOD1 (G93A) develop a dominantly inherited adult-onset paralytic disorder that replicates many of the clinical and pathological features of familial ALS. Increased p53 immunoreactivity has been reported in the motor cortex and spinal ventral horns of postmortem tissue from ALS patients. The nuclear phosphoprotein p53 is an important regulator of cellular proliferation, and increasing evidence supports the role of p53 in regulating cellular apoptosis. To assess the role of p53-mediated apoptosis in amyotrophic lateral sclerosis, mice deficient in both p53 alleles (p53-/-) were crossed with transgenic mice expressing the G93A mutant (G93A+), creating novel transgenic knockout mice. The animals (p53 +/+G93A+, p53+/-G93A+, p53-/-G93A+) were examined at regular intervals for cage activity, upper and lower extremity strength, and mortality. At 120 days from birth mice from each genotype were sacrificed, and L2-L3 anterior horn motor neurons were counted. There was no significant difference in time to onset of behavioral decline, mortality, or motor neuron degeneration between the different genotypes. Despite evidence that p53 plays an important role after acute neuronal injury, the current study suggests that p53 is not significantly involved in cell death in the G93A+ transgenic mouse model of familial ALS.
 ...
PMID:Absence of p53: no effect in a transgenic mouse model of familial amyotrophic lateral sclerosis. 1096 97

Molecular mechanisms promoting neuronal death in amyotrophic lateral sclerosis (ALS) were investigated using transgenic mice that overexpressed the G86R mutated form of the Cu/Zn superoxide dismutase (SOD1) gene. We observed: (i) alteration of the Bcl-x/Bax ratio and (ii) activation of the transcription factor p53, as deduced from its location within neuron nuclei. We further demonstrated that ectopic expression of the G86R mutant SOD1 in PC12 cells enhanced both p53 expression and phosphorylation, leading to transcriptional stimulation of p53-responsive genes. These findings provide evidence that the p53 signaling pathway is activated in SOD1-linked familial ALS and may play a causative role in spinal cord neuron apoptosis by modulating the Bcl-x/Bax ratio.
 ...
PMID:Alteration of the Bcl-x/Bax ratio in a transgenic mouse model of amyotrophic lateral sclerosis: evidence for the implication of the p53 signaling pathway. 1096 11

Mutant Cu/Zn superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis (FALS) causes selective motor neuron loss through unknown mechanisms of cell damage. Damaged neurons frequently undergo apoptosis mediated by the p53 cell survival regulator. We therefore studied whether motor neuron disease (MND) in mice expressing the human SOD1 mutant G93A is dependent on p53 by crossing G93A mice with p53-knockout mice. Since p53-/- mice's life expectance is usually shorter (160+/-49 days, n=11) than the time at which the G93A mice die from MND (212+/-50 days, n=7), only a few of the G93A/p53-/- double transgenics were expected to live to experience MND. Nevertheless, four of the 22 G93A/p53-/- mice succumbed to MND after 160+/-28 days, as expected under these conditions of competing death risks if the absence of p53 fails to protect from MND. Thus, MND in mice expressing G93A does not require p53. This conclusion is supported by histology: pre-symptomatic G93A mice display disease-associated vacuoles within the dendrites of motor neurons regardless of p53 status.
 ...
PMID:Motor neuron cell death in a mouse model of FALS is not mediated by the p53 cell survival regulator. 1101 Oct 20

Several groups have reported pro-apoptotic alteration of gene expression in Down's syndrome (DS) brains. Aged DS brains manifest a similar neuropathology to Alzheimer's disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although it is controversial if neurodegenerative processes play a pathological role in DS brains, evidence such as cortical neurons from fetal DS brains showing vulnerability to cell death when compared with neurons from control subjects supports this point of view. In this chapter, we review the reports that demonstrate pro-apoptotic alteration of gene expression in DS brains. In addition to the pathogenic genes on chromosome 21, such as amyloid precursor protein (APP) and CuZn-superoxide dismutase (SOD1), other genes which associate with p53, or with processes for protein folding have been frequently found.
 ...
PMID:Alteration of gene expression in Down's syndrome (DS) brains: its significance in neurodegeneration. 1177 59

In this study, inducible nitric oxide synthase (iNOS) expression in a series of 158 human primary brain tumors was analyzed. To gain some insight into the biological significance of iNOS expression in tumor cells, comparative immunohistochemical analyses were employed to characterize the expression of iNOS, superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein in these cells. Sixteen (39.0%) of the 41 glioblastoma multiforme (GBM) specimens showed iNOS immunoreactivity. Positive immunoreactions with iNOS were also detected in 2/8 anaplastic astrocytomas, 1/17 astrocytomas, 1/14 medulloblastomas and 1/11 primitive neuroectodermal tumors, but no positive reactions were observed in oligodendrogliomas (0/11), ependymomas (0/5), schwannomas (0/21), meningiomas (0/23) or pituitary adenomas (0/7). The MIB-1 labeling index of GBMs that expressed iNOS was significantly higher than that of GBMs that did not (0.025< P <0.05, Wilcoxon rank-sum test). Unlike iNOS-negative tumors, all iNOS-positive tumors coexpressed SOD1 or SOD2. In particular, there was a significant correlation between iNOS induction and SOD1 expression (P =1.65x10(-10), Fisher's exact test) in GBM specimens. There was no significant relationship between iNOS and p53 protein in any type of primary brain tumor (P >0.05, Fisher's exact test). No significant immunohistochemical reactions with iNOS, MIB-1 or p53 protein were observed in normal brain tissue sections. We conclude that primary brain tumors express iNOS, and that iNOS expression in brain tumor cells may depend, in part, on cellular proliferation potential. Based on the fact that SOD1 scavenges oxidative-stress species originating from large amounts of nitric oxide (NO) produced by iNOS, iNOS-expressing brain tumor cells may protect themselves against NO cytotoxicity by overinducing SOD1.
 ...
PMID:Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationships of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein. 1262 86

Reactive oxygen species (ROS) such as superoxide radicals are responsible for the pathogenesis of various human diseases. ROS are generated during normal metabolic process in all of the oxygen-utilizing organisms. The copper-zinc-containing SOD (SOD1) acts as a major defense against ROS by detoxifying the superoxide anion. In model organisms, SOD1 has been shown to play a role in the aging process. However, the exact role of the SOD1 protein in the human aging process remains to be resolved. We show that SOD1 RNA interference (RNAi) induces senescence in normal human fibroblasts. This premature senescence depends on p53 induction. In contrast, in human fibroblastic cells with inactivated p53, the SOD1 RNAi is without effect. Surprisingly, in cancer cells (HeLa), the SOD1 RNAi induces cell death rather then senescence. Together, these findings support the notion that in normal human cells the SOD1 protein may play a role in the regulation of cellular lifespan by p53 and may also regulate the death signals in cancer cells.
 ...
PMID:Superoxide dismutase 1 knock-down induces senescence in human fibroblasts. 1287 78

Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute to aging. To investigate the role of cellular senescence in aging it is necessary to define the time-dependent molecular events by which it is characterized. Here we investigated changes in levels of key proteins involved in cell cycle regulation, DNA replication, and stress resistance in senescing human fibroblasts following oxidative stress. An immediate response in stressed cells was dephosphorylation of retinoblastoma (Rb) and cessation of DNA synthesis. This was followed by sequential induction of p53, p21, and p16. Increase in hypophosphorylated Rb and induction of p53 and p21 by a single stress treatment was transient, whereas sustained induction or dephosphorylation were achieved by a second stress. Down-regulation of the critical DNA replication initiation factor Cdc6 occurred early after stress concurring with p53 induction, and was followed by a decrease in Mcm2 levels. A late event in the stress-induced molecular sequence was the induction of SOD1, catalase, and HSP27 coinciding with development of the fully senescent phenotype. Our data suggest that loss of proliferative capacity in oxidatively stressed cells is a multistep process regulated by time-dependent molecular events that may play differential roles in induction and maintenance of cellular senescence.
 ...
PMID:Loss of proliferative capacity and induction of senescence in oxidatively stressed human fibroblasts. 1537 61

The tumor suppressor gene p53 plays an important role in the regulation of apoptosis through transcriptional activation of cell cycle control. Degradation of p53 hinders its role in apoptosis regulation. Recent studies have shown that MDM2-mediated ubiquitylation and the ubiquitin-proteasome system are critical regulating systems of p53 ubiquitylation. However, the mechanism regulating p53-mediated neuronal apoptosis after cerebral ischemia remains unknown. We examined the MDM2 pathway and the ubiquitin-proteasome system using a transient focal cerebral ischemia (tFCI) model and analyzed the interaction between p53 regulation and superoxide using copper/zinc superoxide dismutase (SOD1) transgenic mice after tFCI. p53 degradation and ubiquitylation were detected after tFCI. The accumulation of ubiquitylated p53 was inhibited and p53 degradation was facilitated by SOD1. Nuclear translocation and MDM2/Akt interaction were detected after tFCI and were inhibited by phosphatidylinositol 3-kinase inhibition and promoted by SOD1. Cytosolic translocation of the p53/MDM2 complex was detected after tFCI and was promoted by SOD1. Moreover, accumulation of multiubiquitin chains and direct oxidative injury to a proteasome were detected and inhibited by SOD1 after tFCI. These results suggest that SOD1 promotes the MDM2 pathway and the ubiquitin-proteasome system after tFCI and that production of reactive oxygen species after tFCI prevents p53 degradation by inhibiting both systems.
 ...
PMID:Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitin-proteasome system during reperfusion after stroke: role of oxidative stress. 1567 28


1 2 3 4 5 6 7 8 Next >>