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)

Proline dehydrogenase (PRODH) and Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH) catalyze the two-step oxidation of proline to glutamate. They are distinct monofunctional enzymes in all eukaryotes and some bacteria but are fused into bifunctional enzymes known as proline utilization A (PutA) in other bacteria. Here we report the first structure and biochemical data for a monofunctional PRODH. The 2.0-A resolution structure of Thermus thermophilus PRODH reveals a distorted (betaalpha)(8) barrel catalytic core domain and a hydrophobic alpha-helical domain located above the carboxyl-terminal ends of the strands of the barrel. Although the catalytic core is similar to that of the PutA PRODH domain, the FAD conformation of T. thermophilus PRODH is remarkably different and likely reflects unique requirements for membrane association and communication with P5CDH. Also, the FAD of T. thermophilus PRODH is highly solvent-exposed compared with PutA due to a 4-A shift of helix 8. Structure-based sequence analysis of the PutA/PRODH family led us to identify nine conserved motifs involved in cofactor and substrate recognition. Biochemical studies show that the midpoint potential of the FAD is -75 mV and the kinetic parameters for proline are K(m) = 27 mm and k(cat) = 13 s(-1). 3,4-Dehydro-l-proline was found to be an efficient substrate, and l-tetrahydro-2-furoic acid is a competitive inhibitor (K(I) = 1.0 mm). Finally, we demonstrate that T. thermophilus PRODH reacts with O(2) producing superoxide. This is significant because superoxide production underlies the role of human PRODH in p53-mediated apoptosis, implying commonalities between eukaryotic and bacterial monofunctional PRODHs.
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PMID:Structure and kinetics of monofunctional proline dehydrogenase from Thermus thermophilus. 1734 8

The learning and memory impairment of presenilin 2 transgenic mice was mentioned previously. In this study, exposing the presenilin 2 transfected PC12 cells to the 50 microM Abeta(25-35), 30 mM l-glutamate and 50 microM H(2)O(2) resulted in significant increase 8-oxodG and p53 levels of the cells expressing the mutant gene. The increase was also found in the mutant presenilin 2 transgenic mice brains age-dependently in comparison to that in the wild-type presenilin 2-transgenic mice and non-transgenic ones. These findings indicated that mutant presenilin 2 clearly increases oxidative stress and p53 expression, which could be implicated in promoting mutant presenilin 2-induced neurodegeneration in Alzheimer's disease, and the influence of mutant presenilin 2 in Alzheimer's disease may be brain regional and age related effects.
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PMID:Mutant presenilin 2 increased oxidative stress and p53 expression in neuronal cells. 1741 5

Acute and chronic neurodegeneration, for example, following brain injury or Alzheimer's disease, is characterized by programmed death of neuronal cells. The present study addresses the role and interaction of p53- and NF-kappaB-dependent mechanisms in delayed neurodegeneration following traumatic brain injury (TBI). After experimental TBI in mice p53 rapidly accumulated in the injured brain tissue and translocated to the nucleus of damaged neurons, whereas NF-kappaB transcriptional activity simultaneously declined. Post-traumatic neurodegeneration correlated with the increase in p53 levels and was significantly reduced by the selective p53 inhibitor pifithrin-alpha (PFT). Strikingly, this protective effect was observed even when PFT treatment was delayed up to 6 h after trauma. Inhibition of p53 activity resulted in the concomitant increase in NF-kappaB transcriptional activity and upregulation of NF-kappaB-target proteins, for example X-chromosomal-linked inhibitor of apoptosis (XIAP). It is interesting to note that inhibition of XIAP abolished the neuroprotective effects of PFT in cultured neurons exposed to camptothecin, glutamate, or oxygen glucose deprivation. In conclusion, delayed neuronal cell death after brain trauma is mediated by p53-dependent mechanisms that involve inhibition of NF-kappaB transcriptional activity. Hence, p53 inhibition provides a promising approach for the treatment of acute brain injury, since it blocks apoptotic pathways and concomitantly triggers survival signaling with a therapeutic window relevant for clinical applications.
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PMID:Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-kappaB transcriptional activity. 1746 22

Antagonists at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors limit growth of human cancers in vitro. However, the mechanism of anticancer action of AMPA antagonists is not known. Here we report that the AMPA antagonists GYKI 52466 and CFM-2 inhibit the extracellular signal regulated kinase (ERK1/2) pathway, an intracellular signaling cascade which is activated by growth factors and controls proliferation of lung adenocarcinoma cells. AMPA antagonists reduced phosphorylation of cAMP-responsive element binding protein (CREB), suppressed expression of cyclin D1, upregulated the cell cycle regulators and tumor suppressor proteins p21 and p53 and decreased number of lung adenocarcinoma cells in G2 and S phases of the cell cycle. These findings reveal potential mechanism of antiproliferative action of AMPA antagonists and indicate that this class of compounds may be useful in the therapy of human cancers.
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PMID:AMPA antagonists inhibit the extracellular signal regulated kinase pathway and suppress lung cancer growth. 1805 66

Disruption of endoplasmic reticulum (ER) Ca2+ homeostasis and ER dysfunction have been suggested to contribute to excitotoxic and ischaemic neuronal injury. Previously, we have characterized the neural transcriptome following ER stress and identified the BH3-only protein, p53 up-regulated mediator of apoptosis (PUMA), as a central mediator of ER stress toxicity. In this study, we investigated the effects of excitotoxic injury on ER Ca2+ levels and induction of ER stress responses in models of glutamate- and NMDA-induced excitotoxic apoptosis. While exposure to the ER stressor tunicamycin induced an ER stress response in cerebellar granule neurons, transcriptional activation of targets of the ER stress response, including PUMA, were absent following glutamate-induced apoptosis. Confocal imaging revealed no long-term changes in the ER Ca2+ level in response to glutamate. Murine cortical neurons and organotypic hippocampal slice cultures from PUMA+/+ and PUMA-/- animals provided no evidence of ER stress and did not differ in their sensitivity to NMDA. Finally, NMDA-induced excitotoxic apoptosis in vivo was not associated with ER stress, nor did deficiency in PUMA alleviate the injury induced. Our data suggest that NMDA receptor-mediated excitotoxic apoptosis occurs in vitro and in vivo in an ER stress and PUMA independent manner.
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PMID:NMDA receptor-mediated excitotoxic neuronal apoptosis in vitro and in vivo occurs in an ER stress and PUMA independent manner. 1808 54

Proline and hydroxyproline are metabolized by distinct pathways. Proline is important for protein synthesis, as a source of glutamate, arginine, and tricarboxylic acid cycle intermediates, and for participating in a metabolic cycle that shuttles redox equivalents between mitochondria and cytosol. Hydroxyproline, in contrast, is not reutilized for protein synthesis. The first steps in the degradation of proline and hydroxyproline are catalyzed by proline oxidase (POX) and hydroxyproline oxidase (OH-POX), respectively. Because it is well documented that POX is induced by p53 and plays a role in apoptosis, we considered whether OH-POX also participates in the response to cytotoxic stress. In LoVo and RKO cells, which respond to adriamycin with a p53-mediated induction of POX and generation of reactive oxygen species, we found that adriamycin also induced OH-POX gene expression and markedly increased OH-POX catalytic activity, and this increase in activity was not observed in the cell lines HT29 and HCT15, which do not have a functional p53. We also observed an increase in reactive oxygen species generation and activation of caspase-9 with adriamycin in a hydroxyproline-dependent manner. Therefore, we hypothesize that OH-POX plays a role analogous to POX in growth regulation, ROS generation, and activation of the apoptotic cascade.
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PMID:A novel function for hydroxyproline oxidase in apoptosis through generation of reactive oxygen species. 1828

A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.
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PMID:[The role for oxidative stress in neurodegenerative diseases]. 1830 64

Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most significant neurodegenerative disorders in the developed world. However, although these diseases were described almost a century ago, the molecular mechanisms that lead to the neuronal cell death associated with these diseases are not yet clear, and vigorous research efforts have failed to identify effective treatment options. In the present review, we evaluate the potential mechanisms underlying apoptosis and neuronal death in neurodegenerative disorders. A role for mitochondria in the release of proapoptotic proteins, such as cytochrome c and apoptosis-inducing factor (AIF) etc., is discussed along with key processes involving oxidative stress and activation of glutamate receptors. We also deliberate the implication of DNA damage, primarily p53 induction and reentry in the cell cycle. Finally, we postulate that multitargeting therapies comprising antioxidants, cell cycle inhibitors and modulating agents of COX-2 or c-JUN kinase pathways could be suitable strategies to prevent or delay the process of neuronal cell death in neurodegenerative disorders. Thus, the aim of this review is to discuss the pathways involved in the pathogenesis of neurodegenerative diseases such as AD, PD and Huntington's disease (HD). Furthermore, current and future pharmacotherapeutics will be considered.
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PMID:Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches. 1838 97

Mammalian Delta(1)-pyrroline-5-carboxylate synthase (P5CS) is a bifunctional ATP- and NAD(P)H-dependent mitochondrial enzyme that catalyzes the coupled phosphorylation and reduction-conversion of L: -glutamate to P5C, a pivotal step in the biosynthesis of L: -proline, L: -ornithine and L: -arginine. Previously, we reported cloning and characterization of two P5CS transcript variants generated by exon sliding that encode two protein isoforms differing only by a two amino acid-insert at the N-terminus of the gamma-glutamyl kinase active site. The short form (P5CS.short) is highly expressed in the gut and is inhibited by ornithine. In contrast, the long form (P5CS.long) is expressed ubiquitously and is insensitive to ornithine. Interestingly, we found that all the established human cell lines we have studied expressed P5CS.long but not P5CS.short. In addition, expression of P5CS.long can be modulated by hormones: downregulation by hydrocortisone and dexamethasone and upregulation by estradiol, for example. Using a quantitative proteomic approach, we showed that P5CS.long is upregulated by p53 in p53-induced apoptosis in DLD-1 colorectal cancer cells. Functional genomic analysis confirmed that there are two p53-binding consensus sequences in the promoter region and in the intron 1 of the human P5CS gene. Interestingly, overexpression of P5CS by adenoviruses harboring P5CS.long or P5CS.short in various cell types has no effect on cell growth or survival. It would be of importance to further investigate the role of P5CS as a p53 downstream effector and how P5CS.short expression is regulated by hormones and factors of alternative splicing in cells isolated from model animals.
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PMID:Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. 1840 42

Pinocembrin is the most abundant flavonoids in propolis, and has been proven to have antioxidant, antibacterial and anti-inflammatory property. To assess the protective effects of pinocembrin on neurons, SH-SY5Y neuronal cells were pretreated with pinocembrin for 2 h followed by co-treatment with glutamate (2 mM) for 12 h. Cell viability was determined by(3,4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide assay, and apoptosis was confirmed by cell morphology, capillary zone electrophoresis and flow cytometry assay. Cell morphology was evaluated with Hoechst33258/PI dye. Treatment with pinocembrin (10(-5), 10(-6), 10(-7) mol/l) increased cell viability dose-dependently, inhibited LDH release and attenuated apoptosis. Intracellular free [Ca(2+)] was increased after glutamate exposure, and this increase was attenuated in cells treated with pinocembrin. bax mRNA expression increased remarkably following glutamate exposure and pinocembrin treatment manifested a reduction effect. bcl-2 mRNA expression changes were not detected in groups with or without pinocembrin. Western blotting results indicated that pinocembrin treatment reduced the expression of Bax and had no effect on Bcl-2, thus decreased the Bax-Bcl-2 ratio, which is in consistent with the gene expression result. Pinocembrin could also down-regulate the expression of p53 protein, and inhibit the release of cytochrome c from mitochondria to cytosol. Thus we conclude that pinocembrin exerts its neuroprotective effects in glutamate injury model partly by inhibiting p53 expression, thus Bax-Bcl-2 ratio, and the release of cytochrome c.
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PMID:Pinocembrin prevents glutamate-induced apoptosis in SH-SY5Y neuronal cells via decrease of bax/bcl-2 ratio. 1862 18


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