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)

Cowden syndrome is an autosomal dominant condition of multiple hamartomas. Patients with this phakomatosis have an increased risk of breast cancer and thyroid tumours. Lhermitte-Duclos disease is usually a sporadic condition of cerebellar ganglion cell hypertrophy, ataxia, mental retardation, and self-limited seizure disorder. We describe a three generation family with Cowden syndrome and Lhermitte-Duclos disease. Karyotyping performed on the peripheral lymphocytes of the proband and her affected mother showed a 46,XX complement. Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this family.
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PMID:Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? 807 72

The functionality of the p53-mediated pathway, activated in response to DNA damage, has been assessed in primary fibroblast cell cultures and Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Nijmegen breakage syndrome (NBS) patients. This autosomal recessive disease is characterized by microcephaly, growth and mental retardation, chromosomal instability, radiosensitivity, and high cancer incidence. The recent mapping of the NBS gene to chromosome 8q21 demonstrates that NBS is genetically distinct from ataxia telangiectasia (AT). Changes in p53 protein levels were significantly reduced and delayed in all the NBS fibroblast cell cultures and lymphoblastoid cell lines examined compared to normal cultures over a 4-h period postirradiation (5 Gy). The transcriptional activation of p21(WAF1/CIP1) mRNA was also lower in 12 NBS fibroblast cultures examined. In agreement with an abrogated p53 function, NBS cells exposed to ionizing radiation show an abnormal cell cycle arrest at G1-S and a prolonged accumulation of cells in the G2 phase. In contrast, exposure to the alkylating agent methyl methanesulfonate results in similar increases of p53 and p21(WAF1/CIP1) mRNA in both cell types. The ATM gene transcript was found to be expressed at similar levels in NBS and normal cells, whereas it was strongly reduced in the AT homozygote cells examined. These results suggest that the ATM gene product cannot substitute for that of the NBS gene in the signaling of cellular damage produced by ionizing radiation and that both are involved in the activation of p53. The suboptimal p53-mediated response could contribute to the high cancer risk and radiosensitivity seen in NBS patients.
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PMID:Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation. 927 79

CBP and its homolog p300 are large nuclear molecules that coordinate a variety of transcriptional pathways with chromatin remodeling. They interact with transcriptional activators as well as repressors, direct chromatin-mediated transcription, function in TP53-mediated apoptosis, and participate in terminal differentiation of certain tissue types. Recent evidence suggests that the demand for CBP/p300 is greater than the supply, and that competition for CBP/p300 might play an important role in cell growth regulation. Alterations of the human CBP gene have been implicated in hematological malignancies as well as in congenital malformation and mental retardation. Likewise, the p300 gene has been recently implicated in leukemia and mutations in both alleles have been observed in gastric and colorectal carcinomas. The role of these proteins in human disease coupled with biochemical evidence suggests that CBP and p300 are tumor suppressor proteins essential in cell-cycle control, cellular differentiation and human development.
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PMID:Conjunction dysfunction: CBP/p300 in human disease. 961 1

In Down syndrome (DS), enhanced apoptosis (programmed cell death) may play a role in the pathogenesis of characteristic mental retardation and precocious dementia of Alzheimer-type. Upregulation of p53 and APO-1/Fas (CD95) precedes apoptosis in many cell types, and a potential role for these molecules has already been demonstrated in Alzheimer's disease (AD) and several other neurodegenerative diseases. We measured p53 and APO-1/Fas (CD95) protein in four different regions of cerebral cortex and cerebellum in nine adult DS patients with Alzheimer-like neuropathologic lesions compared to nine controls. Quantitative ELISA demonstrated higher frontal lobe (mean+/-SD: 0.10+0.035 vs. 0.041+/-0.016 ng/mg protein), temporal lobe (0.062+/-0.021 vs. 0.032+/-0.019 ng/mg protein) and cerebellar levels (0.078+/-0.030 vs. 0.039+/-0.032 ng/mg protein) of p53 protein, and higher temporal lobe (mean+/-SD: 12.3+/-4.3 vs. 5.3+/-2.0 U/mg protein) and cerebellar levels (5.9+/-1.4 vs. 2.9+/-1.1 U/mg protein) of APO-1/Fas (CD95) protein. The results suggest that p53- or APO-1/Fas (CD95)-associated apoptosis may be an important feature of neurodegeneration in DS.
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PMID:Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome. 1002 87

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

In Down syndrome, enhanced apoptosis (programmed cell death) may play a role in the pathogenesis of characteristic early mental retardation and precocious neurodegeneration of Alzheimer type. Various apoptosis-associated proteins (Bax, Bcl-2, Fas, p53, Hsp70, neuronal apoptosis inhibitory protein-like immunoreactivity) were investigated in four different cortical regions and the cerebellum of one fetal Down syndrome (35 weeks' gestation) postmortem brain sample compared with a control brain sample. The most impressive finding was an at least fivefold elevation of Bax protein together with decreased Bcl-2 values in all Down syndrome cerebral regions investigated. In addition, antiapoptotic, presumably caspase-inhibitory, principles like heat shock protein 70 and neuronal apoptosis inhibitory protein were also reduced. Whereas Fas protein, an important member of receptor-mediated apoptosis, was inconsistently altered, a rather surprising finding was reduced proapoptotic, regulatory protein p53 in four of five regions. The findings are in good agreement with the proposed role of the Bcl-2 protein family in regulating developmental (naturally occurring) apoptotic neuronal death and further suggest that developmental apoptosis may be inappropriately commandeered by so far undefined pathologic processes in Down syndrome.
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PMID:Evidence for apoptosis in the fetal Down syndrome brain. 1141 11

Angelman syndrome (AS), characterized by motor dysfunction, mental retardation, and seizures, is caused by several genetic etiologies involving chromosome 15q11-q13, including mutations of the UBE3A gene. UBE3A encodes UBE3A/E6-AP, a ubiquitin-protein ligase, and shows brain-specific imprinting, with brain expression predominantly from the maternal allele. Lack of a functional maternal allele of UBE3A causes AS. In order to understand the causal relationship between maternal UBE3A mutations and AS, we have constructed a mouse model with targeted inactivation of Ube3a. The inactive allele contains a lacZ reporter gene for analysis of brain-specific imprinting. Maternal, but not paternal, transmission of the targeted allele leads to beta-galactosidase activity in hippocampal and cerebellar neurons. Maternal inheritance of the Ube3a mutant allele also causes impaired performance in tests of motor function and spatial learning, as well as abnormal hippocampal EEG recordings. As predicted from the dependence of UBE3A-mediated ubiquitination of p53 on HPV E6 protein, our maternal-deficient mice show normal brain p53 levels.
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PMID:Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. 1189 68

Down syndrome (trisomy of chromosome 21) (DS) is the most common genetic cause of mental retardation. In our study we employed immunoblotting to evaluate protein expression of reduced folate carrier (hRFC), encoded by a gene localised on chromosome 21, in fetal DS brain. We observed increased expression of hRFC-immunoreactive band with an apparent MW of approximately 150 kDa, whereas the other bands (MWs approximately 60 and 50 kDa), were comparable to control. In conclusion, we suggest that aberrant hRFC expression may well have a role in the already observed deterioration of folate metabolism in DS. Moreover, no alterations of expression level of p53 and Sp1, supposed to play a role in the regulation of hRFC, suggest that regulation of hRFC expression in fetal life by these proteins is highly unlikely, at least by changes in their protein level.
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PMID:Increased expression of human reduced folate carrier in fetal Down syndrome brain. 1506 42

Brain formation results from a series of well-timed consecutive waves of cellular proliferation, migration and differentiation. Acute irradiation during pregnancy selectively interferes with these events to result in malformations such as microcephaly, reduced cortical thickness and mental retardation. In the present study we performed a straight-through cDNA-microarray analysis of the developing mouse brain at embryonic day E13, 3 h after in utero exposure to 50 cGy X-radiation. This dataset was used as an indication of genes involved in different pathways that are activated upon early radiation exposure, and for further evaluation using quantitative PCR (qPCR). Microarray and qPCR data revealed that the main activated pathways in irradiated wild-type embryos are involved in the regulation of a p53-mediated pathway that may lead to cell cycle delay/arrest and increased levels of apoptosis. To define whether the transcriptional radiation response was solely p53 mediated, we analysed the expression of cell cycle regulating genes in a Trp53 null mutant. The modulated expression of cell cycle regulating genes such as cyclins and Cdk genes indicated the induction of a cell cycle arrest, without evidence for the onset of apoptosis. Additional gene-expression studies have shown that various E2F transcription factors may be involved in this event. Together, these results provide a detailed view of the different p53-related mechanisms that are triggered in response to ionizing radiation in the developing brain.
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PMID:The role of Trp53 in the transcriptional response to ionizing radiation in the developing brain. 1676 14


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