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)

Alzheimer's disease (AD) has heterogeneous pathology, in part due to the large subset of cases (AD+CVD) with superimposed vascular lesions that are sufficient in number and distribution to accelerate the clinical course of dementia. Brains with AD+CVD have lower densities of neurofibrillary tangles and A beta-amyloid diffuse plaques, and increased numbers of cerebral vessels exhibiting p53-associated apoptosis relative to brains with uncomplicated AD. AD and AD+CVD both exhibit altered expression of the nitric oxide synthase 3 (NOS-III) gene; however, in AD+CVD, reduced NOS-III expression in cerebral vessels is associated with an increased frequency of vascular lesions, vascular smooth muscle cell apoptosis, and A beta-amyloid plaques. In contrast, experimental and spontaneous focal acute and subacute cerebral infarcts are associated with increased NOS-III expression in perifocal neurons, glial cells, cerebrovascular smooth muscle and endothelial cells, and diffuse A beta-amyloid plaque formation. This suggests that ischemic injury and oxidative stress can precipitate NOS-III-mediated cell loss and neurodegeneration. A role for aging-associated impaired mitochondrial function as a contributing factor in AD and CVD is suggested by the reduced levels of mitochondrial protein observed in AD and AD+CVD cortical neurons and vascular smooth muscle and endothelial cells. The aggregate findings suggest that cell loss and neurodegeneration may be mediated by somewhat distinct but overlapping mechanisms in AD and AD+CVD.
 ...
PMID:Aberrant expression of nitric oxide synthase III in Alzheimer's disease: relevance to cerebral vasculopathy and neurodegeneration. 1086 16

Between 1970 and 1998, 90 cases of male breast cancer with available pathological material were retrieved. The disease often presented in aged patients (median--66 years) and as advanced stage (stage III/IV-51%). Excluding stage IV disease, the neoplasia were predominantly ductal invasive carcinomas. NOS (not otherwise specified) (92%), grade 1 and grade 2 (94%), positive for estrogen and progesterone receptors (72% and 74%), negative for androgen receptors (100%), p53 negative (95%), c-erbB-2 negative (88%) and DNA aneuploid (73%). Assessment of disease outcome is determined by stage at time of diagnosis, and axillary lymph node status was the only parameter found to have a statistically significant correlation with either disease-free interval or overall survival (p < 0.001) by multivariate analysis. Clinically useful information on the probability of relapse can be added by determining c-erbB-2 (p = 0.02) and progesterone receptors (p = 0.04) in stage III and tumor ploidy (p = 0.04) in pN1 subgroups of patients.
 ...
PMID:Male breast cancer--a reappraisal of clinical and biologic indicators of prognosis. 1150 6

Protein A (PA) of Staphylococcus aureus has been demonstrated to possess anti-tumor activity against a wide variety of tumors. In the current study we endeavored to obtain a mechanistic insight into PA-mediated Ehrlich's ascites carcinoma (EAC) killing. Our results indicate that PA stimulates generation of nitric oxide (NO) from murine peritoneal macrophages. Nitric oxide in turn induces cytotoxic damage to the tumor cells. Analysis of the morphological features and cell cycle phase distribution pattern of nuclear DNA revealed an induction of apoptosis (appearance of sub-G0/G1 population) in EAC after PA treatment. We have further elaborated the alterations in the expressions of the proto-oncoproteins p53 and Bax, together with a change in the ratio of Bcl-2/Bax in the treated tumor cells, which favor apoptosis. PA-induced apoptosis and changes in the expression of oncoproteins in the tumor cells was prevented by the suppression of NO release by the addition of L-NAME, the competitive NOS inhibitor, suggesting a possible mechanism by which PA exerts its anti-tumor activities involving nitric oxide through the alteration in the expressions of pro-apoptotic proteins.
 ...
PMID:Protein A-activated macrophages induce apoptosis in Ehrlich's ascites carcinoma through a nitric oxide-dependent pathway. 1177 5

The complexity of recognizing the potential contribution of a number of possible predictors of complex disorders is increasingly challenging with the application of large-scale single nucleotide polymorphism (SNP) typing. In the search for putative genetic factors predisposing to coronary artery restenosis following balloon angioplasty, we determined genotypes for 94 SNPs representing 62 candidate genes, in a prospectively assembled cohort of 342 cases and 437 controls. Using a customized coupled-logistic regression procedure accounting for both additive and interactive effects, we identified seven SNPs in seven genes that, together, showed a statistically significant association with restenosis incidence (P <0.0001), accounting for 11.6% of overall variance observed. Among them are candidate genes for cardiovascular pathophysiology (apolipoprotein-species and NOS), inflammatory response (TNF receptor and CD14), and cell-cycle control (p53 and p53-associated protein). Our results emphasize the need to account for complex multi-gene influences and interactions when assessing the molecular pathology of multifactorial medical entities.
 ...
PMID:Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease. 1208 92

Invasive micropapillary carcinoma (IMPCa) of the breast refers to a unique variant of invasive ductal carcinoma, but its biological behavior has not been elucidated well. We analyzed 16 IMPCa cases (10 pure type, six mixed type). The incidence of IMPCa was 1.0% of all primary breast carcinoma. High nuclear grade (75.0%), as well as poorly differentiated histological grade (81.3%), was frequently seen. Lymph node metastases were evident in 92.9% of the examined cases, and about half of them showed more than 10 positive nodes. Comparison between serially experienced invasive ductal carcinoma, not otherwise specified (IDC-NOS), revealed that both high nuclear grade and poor histological grade were significantly more frequent (P < 0001), there was a lower frequency of positive estrogen receptor/progesterone receptor (P < 0.05, P < 0.01), a higher frequency of HER-2 overexpression (P < 0.025), and more frequent lymph node metastases (P < 0.05) in IMPCa. The comparison between lymph node positive IDC-NOS did not show any statistically significant differences in frequency for positive p53, matrix metalloproteinase protein-2 (MMP-2), vascular endothelial growth factor (VEGF) or E-cadherin. However, IMPCa showed a significantly increased number of blood vessels counted by CD34 immunostains (P < 0.05). These results suggest that IMPCa is, at least, the same or more aggressive than lymph node positive cases of IDC-NOS. Hence, not only the high incidence of lymph node metastases but also distant, blood-borne metastases may be important.
 ...
PMID:Invasive micropapillary carcinoma of the breast: clinicopathological and immunohistochemical study. 1472 Jan 38

The gene expressions for macrophage chemoattractant protein-1 (MCP-1), interleukin (IL)-1 beta, IL-2 and p53 were examined by semi-quantitative RT-PCR in corpora lutea (CL) of rabbits during spontaneous luteolysis at days 13, 15, 18 and 22 of pseudopregnancy. In the same luteal tissue, total activity of nitric oxide (NO) synthase (NOS) and genes for both endothelial (eNOS) and inducible (iNOS) isoforms were also analysed. From day 13 to 15, MCP-1 and IL-1 beta mRNA levels rose (P < or = 0.01) almost 2-fold, and the transcript for p53 almost 8-fold, but then all dropped (P < or = 0.05) from day 18 onward. IL-2 mRNA abundance was higher (P < or = 0.01) on day 13 and then gradually declined. During luteolysis, eNOS mRNA decreased 40% (P < or = 0.05) by day 15, but thereafter remained unchanged, while iNOS mRNA was barely detectable and did not show any clear age-related pattern throughout the late luteal stages. Total NOS activity progressively increased (P < or = 0.01) from day 13 to 18 of pseudopregnancy and then dropped to the lowest (P < or = 0.01) levels on day 22. Luteal progesterone content also declined during CL regression from 411 to 17 pg/mg found on days 13 and 22 respectively, in parallel with the decrease in blood progesterone concentrations. These data further support a physiological role of NO as modulator of luteal demise in rabbits. Locally, luteal cytokines may be involved in the up-regulation of NOS activity, while downstream NO may inhibit steroroidogenesis and induce expression of p53 gene after removal of the protective action of progesterone.
 ...
PMID:Expression patterns of cytokines, p53 and nitric oxide synthase isoenzymes in corpora lutea of pseudopregnant rabbits during spontaneous luteolysis. 1505 89

Nitric oxide (NO) has been shown to inhibit migration of cells in which various matrix metalloproteinases (MMPs) are involved. The underlying molecular mechanisms of this inhibition remain elusive. Endothelial cells (ECs) constitutively produce MMP-2. The effect of NO on MMP-2 expression was examined. A dose-dependent inhibition of MMP-2 mRNA level was demonstrated in ECs treated with NO. ECs infected with adenovirus carrying endothelial NO synthase (Ade-NOS) reduced MMP-2 expression. The inhibitory effect of NO on MMP-2 expression was a transcriptional event because NO reduced MMP-2 promoter activity. NO treatment of ECs consequently suppressed MMP-2 secretion revealed by zymographic assay. Functional analysis of MMP-2 promoter (1716 base pairs) indicated that the p53-binding site (-1659 to -1629) was crucial for MMP-2 promoter activity. Activating transcription factor 3 (ATF3) has been reported to act as a transcriptional repressor for p53. ECs treated with NO induced ATF3 expression. Consistently, Ade-NOS-infected ECs showed an increase of ATF3 level. Moreover, ECs either over-expressed ATF3 or, when treated with an ATF3 activator (MG-132; carbobenzoxy-l-leucyl-l-leucyl-l-leucinal), resulted in a repression of MMP-2 promoter activity. Because of MMP-2 suppression by NO, ECs treated with NO inhibited endothelial migration, a phenomenon similar to that of ECs treated with MMP-2 antibody or MG-132. These results indicate that NO-attenuating endothelial migration is mediated at least in part by its reduction of MMP-2 expression via the up-regulation of ATF3. This study provides a molecular basis that supports the notion that NO acts as a negative regulator in endothelial migration.
 ...
PMID:Nitric oxide inhibits matrix metalloproteinase-2 expression via the induction of activating transcription factor 3 in endothelial cells. 1510 41

Human diseases develop by complex mutual relationships of genetic and environmental factors. In inherited diseases, DNA diagnosis of the disease-causing genes provides a confirmation of the disease. On the other hand, DNA diagnosis of the disease-sensitive genes in multifactorial diseases, such as the lifestyle-related diseases (common diseases), provides the risk of developing the disease. Two new technologies are being used for DNA diagnosis in the clinic. The first is called Invader Technology and is a non-PCR method and is useful for detecting well-known genetic variations in large samples efficiently. We have developed a method to quantify the heteroplasmy of mitochondrial DNA mutations by this technique. The second technique, called WAVE, uses denaturing high-performance liquid chromatography to screen for mutations in a large number of samples automatically and efficiently. Clinical DNA diagnoses are divided into those for single genetic diseases and those for multifactorial diseases. The purposes for DNA diagnosis in single genetic diseases are: 1) to propose a new clinical classification of the disease, such as TGFB1-related corneal dystrophy or retinitis pigmentosa, based on the genotypes; 2) to confirm a clinical diagnosis, such as Leber's hereditary optic neuropathy (LHON); and 3) to provide an early diagnosis before the development of the disease and thus provide an opportunity to start early treatment. For example, a family history of glaucoma is one of the risk factors for developing glaucoma. The frequency of mutations in the glaucoma genes, myocilin and optineurin, were found to be about 3% and 0.25%, respectively, in Japanese. The significance of DNA diagnosis in multifactorial diseases is that it provides a risk diagnosis for an individual. Single nucleotide polymorphisms (SNPs) of disease-sensitive genes are associated with only a 2- to 3-fold risk of developing the disease. A case-control association study was performed using many SNP markers to identify glaucoma-sensitive genes. A total of 671 Japanese individuals, 201 POAG patients, 234 NTG patients, and 236 normal controls were examined. Fifty-two SNPs in the 38 genes were examined to identify the glaucoma-sensitive genes as candidate genes, and SNPs in AT 1, AT 2, PON 1, GSTT 1, NOS 3, and EDN 1 were associated with glaucoma statistically. Mitochondrial (mt) DNA mutations associated with LHON might be risk factors for open-angle glaucoma, because abnormal optic disc excavations are also found in LHON patients. A total of 651 blood samples were screened for 6 LHON-associated mutations with the Invader assay. Seven patients had one of the five mutations, but none had developed LHON. The 5 mutations were not identified in 236 normal controls. MtDNA mutations may make the optic disc more susceptible to damage in glaucoma patients. The clinical variability in LHON patients suggests that the disease most likely results from multi factorial mechanisms. To determine whether genetic polymorphisms for oxidative stress and apoptosis cause clinical variability in patients with LHON, 12 polymorphisms in 10 genes were analyzed in 87 patients with the 11778 mutation in relation to the age at onset and final visual acuity. LHON patients carrying homozygous His 113 in the EPHX1 gene or homozygous Arg 72 in the TP53 gene developed the disease earlier than those without this genotype. Thus, nuclear genetic polymorphisms related to oxidative stress or apoptosis may modify the age of LHON onset. A clinical trial of 38 healthy volunteers without systemic diseases or eye diseases was performed using an angiotensin II receptor blocker (candesartan cilexetil) as an alternative drug for lowering intraocular pressure (IOP). After a single oral dose of candesartan cilexetil, the IOP fell significantly for 24 hr. There was no association between the effects of oral candesartan cilexetil and the three SNPs in the AT 1 gene. In the 21th century, DNA diagnosis for multifactorial diseases will be required to determine the treatment plan for individuals or to prevent diseases. We have developed a panel of tests by Invader assay for clinical use to detect mutations in the myocilin gene or in LHON. In the future, we will develop a panel to detect SNPs in the glaucoma-sensitive genes to diagnose individuals at risk for developing glaucoma. Such information is expected to help develop new medications.
 ...
PMID:[DNA diagnosis in the age of individual made-to-order medications]. 1565 90

The mechanisms of injury- and disease-related degeneration of motor neurons (MNs) need clarification. Unilateral avulsion of the sciatic nerve in the mouse induces apoptosis of spinal MNs that is p53 and Bax dependent. We tested the hypothesis that MN apoptosis is Fas death receptor dependent and triggered by nitric oxide (NO)- and superoxide-mediated damage to DNA. MNs in mice lacking functional Fas receptor and Fas ligand were protected from apoptosis. Fas protein levels and cleaved caspase-8 increased in MNs after injury. Fas upregulation was p53 dependent. MNs in mice deficient in neuronal NO synthase (nNOS) and inducible NOS (iNOS) resisted apoptosis. After injury, MNs increased nNOS protein but decreased iNOS protein; however, iNOS contributed more than nNOS to basal and injury-induced levels of NADPH diaphorase activity in MNs. NO and peroxynitrite (ONOO-) fluorescence increased in injured MNs, as did nitrotyrosine staining of MNs. DNA damage, assessed as 8-hydroxy-2-deoxyguanosine and single-stranded DNA, accumulated within injured MNs and was attenuated by nNOS and iNOS deficiency. nNOS deficiency increased DNA repair protein oxoguanine DNA-glycosylase, whereas iNOS deficiency blocked diaphorase activity. MN apoptosis was blocked by the antioxidant Trolox and by overexpression of wild-type human superoxide dismutase-1 (SOD1). In contrast, injured MNs in mice harboring mutant human SOD1 had upregulated Fas and iNOS, escalated DNA damage, and accelerated and increased MN degeneration and underwent necrosis instead of apoptosis. Thus, adult spinal MN apoptosis is mediated by upstream NO and ONOO- genotoxicity and downstream p53 and Fas activation and is shifted to necrosis by mutant SOD1.
 ...
PMID:Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. 1600 Jun 35

Glucose uptake and energy metabolism in the brain are regulated by insulin and insulin-like growth factors (IGF). Recent studies demonstrated progressive deficiencies in brain insulin and IGF production and responsiveness, and linked these abnormalities to acetylcholine deficiency in Alzheimer's disease (AD). We extended this line of research by attempting to correlate the deficits in insulin/IGF signaling and energy production with mitochondrial dysfunction, oxidative injury, and compensatory cyto-protective responses in brains with different Braak Stage severities of AD. Real time quantitative RT-PCR analysis of frontal lobe tissue demonstrated significantly reduced expression of mitochondria-encoded Complex IV and V genes, with relative preservation of genes encoding Complexes I, II and III. In addition, AD was associated with significantly increased expression of the p53 pro-apoptosis gene, all 3 isoforms of nitric oxide synthase (NOS 1-3), and NADPH-oxidase (NOX) 1 and NOX 3, beginning early in the course of disease. Activation of cyto-protective mechanisms in AD brains was limited since the expression levels of uncoupling protein (UCP) 2, 4, and 5, and peroxisome-proliferator activated receptor (PPAR) alpha and delta genes were significantly reduced, whereas PPAR-gamma expression was selectively increased. The results demonstrate that AD is associated with early and striking increases in the molecular indices of oxidative stress, including up-regulation of NOS and NOX genes, which could impair the function of Complexes IV and V within the electron transport chain. The simultaneous reductions in cyto-protective mechanisms (UCP and PPAR), could allow oxidative injury to go unchecked and persist or increase over time. Adopting strategies to reduce the effects of NOS and NOX activities, and improve the actions of UCPs and PPARs may help in the treatment of AD.
 ...
PMID:Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. 1687 64


<< Previous 1 2 3 4 5 6 Next >>