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)

Apoptosis is a mode of cell death in which the cell plays an active role in its own demise. The study of neural apoptosis, the identification of genes controlling apoptosis, and the examination of the mechanisms by which these genes achieve their effects have assumed increasing importance over the past few years. This is because (1) neural apoptosis occurs not only in development, but also in pathophysiological states such as stroke, glutamate toxicity, and beta-amyloid peptide toxicity; (2) genes that control apoptotic cell death, such as bcl-2, p35, p53, and p75NTR, also modulate necrotic neural death in some cases; (3) the emerging mechanisms by which these genes control apoptosis may be relevant for understanding neurodegenerative processes, and for the design of therapeutic agents; and (4) the findings that the cell plays an active role in its own demise, and that specific gene products are involved, suggest that therapeutic intervention may be feasible.
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PMID:Neural apoptosis. 852 56

The finding that intracellular expression of the beta-amyloid protein (Abeta) under a neuron-specific promoter led progressively to degeneration and death of neurons in the brains of transgenic mice provides a unique opportunity to utilize this animal model to both understand the mechanism that underlies neuronal cell death and define the complexity of events which may ensue. We observed a correlation between Abeta accumulation in selective neurons and activation of p53, a protein that has been implicated in the induction of apoptosis. Histological and immunohistochemical evaluations of adjacent brain sections suggest that expression of p53 is accompanied by nuclear DNA fragmentation. In certain regions with marked neuronal cell death, extracellular deposition of A(beta) became evident, together with the local activation of astrocytes. Interestingly, the neuritic structures underlying the Abeta deposits showed altered synaptophysin immunoreactivity and morphologic evidence for damage. This transgenic mouse model suggests that intracellular generation of the Abeta protein not only leads to the death of the neuron but may also functionally impair neighboring neurons as well. It further offers a mechanism whereby neuritic plaques may be derived.
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PMID:Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice. 883 12

Down syndrome is caused by over-expression of genes located within a segment of chromosome 21, termed the Down locus. Down syndrome is associated with developmental abnormalities of the central nervous system that result in mental retardation and age-dependent Alzheimer-type neurodegeneration. Some of the neurodegenerative lesions, including A beta amyloid deposition, apoptotic cell death, and aberrant dendritic arborization, are in part due to constitutively increased expression of genes that encode the amyloid precursor protein, superoxide dismutase I, and S100-beta, and located within the Down locus. However, neurodegeneration in Down syndrome is also associated with aberrant expression of genes that are not linked to the Down locus, including the growth associated protein, GAP-43, nitric oxide synthase 3, neuronal thread protein, and pro-apoptosis genes such as p53, Bax, and interleukin-1 beta-converting enzyme. Increased expression of these non-Down locus genes correlates with proliferation of dystrophic neurites and apoptotic cell death, two important correlates of cognitive impairment in Alzheimer's disease. This article reviews the functional importance of abnormal gene expression in relation to Alzheimer-type neurodegeneration in brains of individuals with Down syndrome.
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PMID:Molecular abnormalities of the brain in Down syndrome: relevance to Alzheimer's neurodegeneration. 1066 65

Down's syndrome (DS), occurring in 0.8 out of 1,000 live births, is a genetic disorder in which an extra portion of chromosome 21 leads to several abnormalities. With respect to the nervous system, it causes mental retardation. It is conceived that abnormal neuronal cell death in development is involved, but there is no direct evidence yet. In addition to developmental brain abnormalities, almost all DS brains over 40 years old manifest a similar pathology to Alzheimer's disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although there was a debate to segregate dementia from underlying mental retardation, at least some portion of DS patients exhibit deteriorated mental status with aging. The mechanism underlying these abnormalities at the molecular level remains to be elucidated. Recently there have been several reports suggesting abnormalities reflecting increased risk to apoptosis in DS brains. Increased expression of several apoptosis-related genes (p53, fas, ratio of bax to bcl-2, GAPDH) in DS brains has been reported. Cultured neurons from both patients and model animals are reportedly more vulnerable to apoptosis. Overproduction of reactive oxygen species and its causative roles for increased apoptosis in DS tissues are suggested. One possible hypothesis is an increased susceptibility to apoptosis due to p53 overactivation in DS brains. A beta 42, a critical peptide for AD pathology from amyloid precursor protein (APP), can be detected in DS brains. A beta 42 is deposited in SP from an early stage, suggesting common molecular mechanisms in DS and AD. Animal models for DS are important in the search of molecular mechanisms. Several types of models are now available. Future DS studies are expected to integrate information from animal models and human tissues.
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PMID:Neuronal cell death in Down's syndrome. 1066 70

Apoptosis of neuronal cells apparently plays a role in Alzheimer's disease (AD). The amyloid beta (Abeta) peptide derived from beta-amyloid precursor protein is found in AD brain in vivo and can induce apoptosis in vitro. While p53 accumulates in cells of AD brain, it is not known if p53 plays an active role in Abeta-induced apoptosis. We show here that inactivation of p53 in two experimental cell lines, either by expression of the papillomavirus E6 protein or by a shift to restrictive temperature, does not affect apoptosis induction by Abeta (25-35), indicating that Abeta induces apoptosis in a p53-independent manner.
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PMID:The amyloid beta peptide abeta (25-35) induces apoptosis independent of p53. 1073 38

We reported previously that many neurodegenerative changes characteristic of apoptosis could be induced by a short fragment of beta-amyloid protein, A(beta31-35), in cultured newborn mice cortical neurons, and that these changes were accompanied with alterations in expression of some genes. This study was designed to examine whether the apoptotic processes and related gene modulations in this model could be affected by coadministration of carbachol by electrophoretic analysis for DNA ladder formation and by RT-PCR assays for genomic modulation. The results showed that (1) simultaneous incubation with carbachol dose- and time-dependently blocked the specific DNA ladder formation induced by exposure to A(beta31-35) and (2) the A(beta31-35)-induced downregulation of bcl-2 and upregulations of bax, p53, and c-fos genes were reversed or ameliorated by the coadministration of carbachol. It is proposed that A(beta31-35)-induced apoptosis can be prevented by carbachol through mechanisms that modulate the expression of related genes.
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PMID:Carbachol blocks beta-amyloid fragment 31-35-induced apoptosis in cultured cortical neurons. 1075 35

Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, are re-expressed in neurons committed to death in response to a variety of insults, including excitotoxins, hypoxia and ischemia, loss of trophic support, or beta-amyloid peptide. In some of these conditions events that are typical of the mid-G1 phase, such as cyclin-dependent kinase 4/6 activation, are required for the induction of neuronal death. In other cases, the cycle must proceed further and recruit steps that are typical of the G1/S transition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. We hypothesize that cell-cycle signaling becomes a mandatory component of neuronal demise when other mechanisms are not enough for neurons to reach the threshold for death. Under this scheme, the death threshold is set by the extent of DNA damage. Whenever the extent of DNA damage is below this threshold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.
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PMID:Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path? 1116 84

To elucidate the mechanisms underlying physiological development and neurodegenerative disorders of the human brain, information about molecular cell biology of human neurons is indispensable. Necdin, which is expressed in postmitotic neurons, binds to viral oncoproteins and the cell-cycle-related transcription factors E2F and p53. Ectopic expression of necdin in proliferative cells suppresses cell division. Necdin is expressed in neurons in phylogenetically old brain areas such as the brain stem and hypothalamus. The human necdin gene, which resides in the chromosome 15q11-q12 region, is not expressed in the Prader-Willi syndrome, suggesting that necdin is responsible for the pathogenesis of this genomic-imprinting-related neurobehavioral disorder. The Alzheimer amyloid precursor protein (APP) is a membrane-bound protein that is abundantly expressed in postmitotic neurons. The proteolytic processing of APP generates A beta, which is deposited in the brains of patients with Alzheimer's disease. APP is strongly expressed in neurons in phylogenetically new brain areas such as human association cortices. When APP is overexpressed in postomitotic neurons differentiated from human embryonal carcinoma by adenovirus-mediated gene transfer, it induces typical apoptosis through caspase-3 activation. Thus APP may be a proapoptotic molecule involved in neuronal death in Alzheimer's disease.
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PMID:[Molecular mechanisms of differentiation and death of human neurons: with special reference to necdin and APP]. 1121

Degeneration and death of neurons is the fundamental process responsible for the clinical manifestations of many different neurological disorders of aging, incuding Alzheimer's disease, Parkinson's disease and stroke. The death of neurons in such disorders involves apoptotic biochemical cascades involving upstream effectors (Par-4, p53 and pro-apoptotic Bcl-2 family members), mitochondrial alterations and caspase activation. Both genetic and environmental factors, and the aging process itself, contribute to intiation of such neuronal apoptosis. For example, mutations in the amyloid precursor protein and presenilin genes can cause Alzheimer's disease, while head injury is a risk factor for both Alzheimer's and Parkinson's diseases. At the cellular level, neuronal apoptosis in neurodegenerative disorders may be triggered by oxidative stress, metabolic compromise and disruption of calcium homeostasis. Neuroprotective (antiapoptotic) signaling pathways involving neurotrophic factors, cytokines and "conditioning responses" can counteract the effects of aging and genetic predisposition in experimental models of neurodegenerative disorders. A better understanding of the molecular underpinnings of neuronal death is leading directly to novel preventative and therapeutic approaches to neurodegenerative disorders.
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PMID:Neurodegenerative disorders and ischemic brain diseases. 1132 Oct 43

Huperzine A, a promising therapeutic agent for Alzheimer's disease, was examined for its potential to antagonize the deleterious neurochemical, structural, and cognitive effects of infusing beta-amyloid protein-(1-40) into the cerebral ventricles of rats. Daily intraperitoneal administration of huperzine A for 12 consecutive days produced significant reversals of the beta-amyloid-induced deficit in learning a water maze task. This treatment also reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by beta-amyloid protein-(1-40). In addition, huperzine A partly reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins and reduced the apoptosis that normally followed beta-amyloid injection. The present findings confirm that huperzine A can alleviate the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid protein-(1-40) in rats. The beneficial effects are not confined to the cholinergic system, but also include favorable changes in the expression of apoptosis-related proteins and in the extent of apoptosis in widespread regions of the brain.
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PMID:Huperzine A attenuates cognitive dysfunction and neuronal degeneration caused by beta-amyloid protein-(1-40) in rat. 1151 30


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