Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The cascade of Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress, mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral Streptozotocin (ic-STZ), that chemical depletion of insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated blood glucose levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, active glycogen synthase kinase 3beta, phospho-tau, ubiquitin, and amyloid-beta. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes.
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PMID:Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. 1662 31

Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinizationAims : To examine invasive head and neck squamous carcinomas for expression of GLUT1, a glucose transporter and marker of increased glucose uptake, glycolytic metabolism and response to tissue hypoxia; p63, a p53 homologue that is a marker of the undifferentiated proliferative basaloid phenotype; and phospho-histone H1, a marker of activation of the cell cycle-promoting cyclin-dependent kinases 1 and 2. Methods : Routinely processed slides from 34 invasive squamous carcinomas, including 25 with intraepithelial components, were immunostained with anti-GLUT1 (Chemicon), anti-p63 (4A4, Santa Cruz), and antiphospho-histone H1 (monoclonal 12D11). Results : In keratinizing carcinomas, all three markers were most commonly immunodetected peripherally, with loss of expression in central keratinized zones. In contrast, in non-keratinizing carcinomas, p63 and phospho-histone H1 expression was most commonly observed throughout tumour nests and anti-GLUT1 stained in a pattern suggestive of hypoxia-induced expression ('antistromal' staining), in which cells at the tumour-stromal interface were GLUT1- and cells in central, perinecrotic zones showed progressive induction of GLUT1. Intraepithelial components also displayed basal and 'antibasal' GLUT1 staining patterns, homologous to the pro- and antistromal patterns in invasive carcinoma; basal patterns in intraepithelial lesions appeared to be more predictive of keratinizing invasive carcinoma and antibasal intraepithelial staining more predictive of non-keratinizing poorly differentiated carcinomas. Conclusions : Keratinizing and non-keratinizing squamous carcinomas differ in expression patterns of GLUT1, p63 and phospho-histone H1. In the former, all three markers were typically suppressed in conjunction with keratinization; in the latter, GLUT1 expression was more likely to occur in a hypoxia-inducible pattern and expression of p63 and phospho-histone H1 was unsuppressed. GLUT1 expression patterns in intraepithelial lesions may be predictive of the differentiation status of the associated invasive carcinoma.
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PMID:Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinization. 1668 88

The glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has been shown to enhance the cell death induced by radiation and other DNA damaging agents selectively in cells with high rates of glycolysis, like cancer cells. While energy linked modification of DNA and cellular repair processes have been suggested as possible mechanisms of sensitization, other effects such as global stress response cannot be excluded. In this pilot study, we have investigated the effect of 2-DG and radiation on the transcriptome in an attempt to elucidate how 2-DG impacts gene expression in undamaged verses irradiation (IR) damaged cells using a human malignant glioma cell line, U-87. Exponentially growing U-87 cells were exposed to various combinations of 2-DG and X-rays and total RNA was isolated four hours after exposure. Gene expression changes were elucidated using Affymetrix GeneChips. As expected, U-87 cells treated with 2-DG showed activation of several endoplasmic reticulum stress response genes. Selective RT-PCR and Western blotting confirmed these gene alterations. Given that glucose deprivation leads to p53 activation and 2-DG led to activation of p53 response genes in our present study (e.g., PMAIP1 and GADD45A), we examined the impact of transient p53 knockdown and observed that induction of PMAIP1 and GADD45A appear to be via p53-independent mechanisms. The majority of gene alterations seen with IR-treatment alone were consistent with previous reports. While most gene alterations seen with 2-DG and IR dual treatment were confirmed in the gene profiles seen with individual (2-DG or IR) treatments, several genes appeared differentially regulated between IR and 2-DG (e.g., DUSP8, IL8, GADD45B). Additionally, gene expression patterns suggested alterations in cell cycle regulation, apoptosis, and cytokine signaling pathways. Taken together, this study provides new insights into how the transcriptome of tumor cells are likely to be affected by a combined stress caused by IR and 2-DG.
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PMID:Altered gene expression induced by ionizing radiation and glycolytic inhibitor 2-deoxy-glucose in a human glioma cell line: implications for radio sensitization. 1688 Jul 34

Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.
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PMID:The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. 1678 27

The p53 tumor suppressor pathway coordinates DNA repair, cell-cycle arrest, apoptosis, and senescence to preserve genomic stability and prevent tumor formation. The discovery of three new target genes for p53 reveals unexpected functions for this tumor suppressor in the regulation of glucose metabolism and autophagy.
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PMID:p53 and metabolism: Inside the TIGAR. 1683 81

Glutamine and glucose are often controlled at low levels in fed-batch strategies to limit ammonia and lactate accumulation and improve productivity of mammalian cell cultures. However, this risks triggering apoptosis if cells are depleted of glutamine or glucose. To examine the apoptosis cascade during glutamine or glucose limitation, the transcriptional profile of FAS, FASL, FADD, FLIP, BAX, p53 and PEG3 in CRL 1606 hybridoma culture was investigated using quantitative real-time PCR. Activities of caspases 2, 3, 8 and 9 were also analyzed. Increase in the activities of the caspases was observed with up-regulation in the expression of FAS (6-8-fold) and PEG3 (2.5-fold), suggesting that the cells experienced apoptotic cell death via both the death receptor and mitochondrial pathways.
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PMID:Glutamine or glucose starvation in hybridoma cultures induces death receptor and mitochondrial apoptotic pathways. 1685 9

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.
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PMID:Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. 1687 64

In the present study, we employed 2-DE to characterize the effect of the acute promyelocytic leukemia (APL)-specific PML-RARalpha fusion protein on the proteome. Differentially expressed proteins, a number of which are related to the cell cycle function, including oncoprotein18 (OP18), heat shock protein70, glucose-regulated protein75, and peptidyl-prolyl isomerase, were identified by MS. Subsequent bioinformatic pathway discovery revealed an integrated network constituting SMARCB1, MYC, and TP53-regulated pathways. The data from the DNA microarray and proteomic experiments demonstrated the correlation between the translocation and higher expression of OP18 at mRNA and protein levels. Transient cotransfection assay revealed that PML-RARalpha is a potent activator of OP18 promoter and this transcriptional activation is retinoic acid sensitive. PML-RARalpha induction also leads to decreased phosphorylation on Ser63 residue of OP18, which is okadaic acid sensitive suggesting the involvement of a phosphatase pathway. Overexpression of a constitutively phosphorylated Ser63 mutant of OP18 in PML-RARalpha expressing APL patient, PR9, and NB4 cells led to a G2/M-phase arrest in contrast to a phosphorylation-deficient Ser63 mutant and untransfected control. Taken together, our results demonstrate the significance of decreased Ser63 phosphorylation of OP18 in PML-RARalpha-mediated effects on cell cycle.
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PMID:Proteomic analysis of acute promyelocytic leukemia: PML-RARalpha leads to decreased phosphorylation of OP18 at serine 63. 1700 4

Rhubarb has been used as a traditional Chinese medicine since ancient times and today it is still present in various herbal preparations. In this review the toxicological and anti-neoplastic potentials of the main anthraquinones from Rhubarb, Rheum palmatum, will be highlighted. It is interesting to note that although the chemical structures of various anthraquinones in this plant are similar, their bioactivities are rather different. The most abundant anthraquinone of rhubarb, emodin, was capable of inhibiting cellular proliferation, induction of apoptosis, and prevention of metastasis. These capabilities are reported to act through tyrosine kinases, phosphoinositol 3-kinase (PI3K), protein kinase C (PKC), NF-kappa B (NF-kappaB), and mitogen-activated protein kinase (MAPK) signaling cascades. Aloe-emodin is another major component in rhubarb found to have anti-tumor properties. Its anti-proliferative property has been demonstrated to be through the p53 and its downstream p21 pathway. Our recent proteomic study also suggests that the molecular targets of these two anthraquinones are different. However, both components were found to be able to potentiate the anti-proliferation of various chemotherapeutic agents. Rhein is the other major rhubarb anthraquinone, although less well studied. This compound could effectively inhibit the uptake of glucose in tumor cells, caused changes in membrane-associated functions and led to cell death. Interestingly, all three major rhubarb anthraquinones were reported to have in vitro phototoxic. This re-evaluation of an old remedy suggests that several bioactive anthraquinones of rhubarb possess promising anti-cancer properties and could have a broad therapeutic potential.
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PMID:Anti-cancer properties of anthraquinones from rhubarb. 1702 20

Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug- or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis and that Hif-1alpha plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1alpha by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1alpha-dependent manner. As GLUT-1 was induced via Hif-1alpha under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1alpha-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.
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PMID:Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. 1704 58


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