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)

Nitric oxide signaling is achieved through both cGMP-dependent and cGMP-independent mechanisms. The latter are exemplified by protein thiol modification followed by subsequent NAD(+)-dependent automodification of the glycolytic enzyme GAPDH, or by mechanisms inducing accumulation of the tumor suppressor gene p53 and causing apoptotic cell death. Both cGMP-independent actions are initiated using NO-releasing compounds and an active LPS/cytokine-inducible NO synthase. NO-synthase inhibitors block the release of NO and hinder downstream signaling mechanisms; they are therefore valuable pharmacological tools linking a defined cellular response to various NO actions. Signal transducing mechanisms elicited by NO can be studied using GAPDH as a representative example of NO-induced protein modification and are grouped as follows: --S-Nitrosylation reactions initiated by NO+ --NAD(+)-dependent, post-translational covalent automodification of GAPDH --Oxidative modification (thiol oxidation) and inhibition of GAPDH by NO-related agents, probably ONOO- GAPDH and several other protein targets may serve as molecular sensors of elevated NO concentrations and may transmit this message through posttranslational modification and oxidation-induced conformational changes as cGMP-independent NO signaling pathways. Toxicity of NO seems to be linked to both apoptosis and necrosis, depending on the chemistry of NO it undergoes in a given biological milieu. Toxicity manifests as a relative excess of NOx, metal-NO interactions, and ONOO- formation in relation to cellular defense systems. Although accumulation of the tumor-suppressor gene product p53 in response to NO opens a regulatory mechanism known to be involved in apoptotic cell death, cGMP-independent signaling pathways remain to be elucidated. As NO-dependent modification of GAPDH would imply down-regulation of glycolysis and concomitant energy production followed by cell death, our data so far do not support this assumption. In recent years, NO has proved to be a beneficial messenger with a potentially toxic activity. It will be challenging to investigate NO biochemistry in closer detail and to elucidate how NO targets biological systems, especially in relation to its pathophysiological role.
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PMID:Protein thiol modification and apoptotic cell death as cGMP-independent nitric oxide (NO) signaling pathways. 853 7

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

Hypoxia limits tumor growth but selects for higher metastatic potential. We tested the functional activity of hypoxia-inducible factor-1 (HIF-1) in prostate cell lines ranging from normal epithelial cells (PrEC), hormone-dependent LNCaP, hormone-independent DU145, PC-3 to highly metastatic PC-3M cancer cell lines. We found that HIF-1-stimulated transcription was the lowest in PrEC and LNCaP cells and the highest in PC-3M cells. The induction by hypoxia of the HIF-1 dependent genes Cap43 and GAPDH was the highest in the most aggressive PC-3M cancer cells. Because these advanced prostate cancer cell lines have lost p53 function, this further shifts a balance from p53 to HIF-1 transcriptional regulation, and a high ratio of HIF-1-dependent:p53-dependent transcription was a marker of the advanced malignant phenotype. Transient transfection of HIF-1alpha expression vector induced transcription from p21 promoter construct in prostate cancer cell lines. Furthermore, hypoxia slightly induced p21 mRNA in these cells. However, neither expression of p21 nor hypoxia caused growth arrest in PC-3M cells. Therefore, high inducibility of HIF-1-dependent genes, loss of p53 functions with high ratio of HIF-1-dependent:p53-dependent transcription, and loss of sensitivity to p21 inhibition is a part of hypoxic phenotype associated with aggressive cancer behavior.
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PMID:Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer. 1105 52

The gene expression pattern of mesothelial cells in vitro was determined after 4 or 12 h exposure to the rat mesothelial, kidney, and thyroid carcinogen and oxidative stressor potassium bromate (KBrO(3)). Gene expression changes observed using cDNA arrays indicated oxidative stress, mitotic arrest, and apoptosis in treated immortalized rat peritoneal mesothelial cells. Increases occurred in oxidative stress responsive genes HO-1, QR, HSP70, GADD45, GADD153, p21(WAF1/CIP16), GST's, GAPDH, TPX, and GPX-1(0); transcriptional regulators c-jun, c-fos, jun B, c-myc, and IkappaB; protein repair components Rdelta, RC10-II, C3, RC-7, HR6B ubiquitin-conjugating enzyme and ubiquitin; DNA repair components PCNA, msh2, and O-6 methylguanine DNA methyltransferase; lipid peroxide excision enzyme PLA2; and apoptogenic components TNFalpha, iNOS1 and FasL. Decreases occurred in bcl-2 (antiapoptotic), bax alpha, bad, and bok (proapoptotic) and cell cycle control elements (cyclins). Cyclin G and p14ink4b (which inhibit entry into cell cycle) were increased. Numerous signal transduction, cell membrane transport, membrane-associated receptor, and fatty acid biosynthesis and repair components were altered. Morphologic endpoints examined were number of mitotic figures, number of apoptotic cells, and antibody-specific localization of HO-1 (which demonstrated increased HO-1 protein expression). PCR analysis confirmed HO-1, p21(waf1/cip1), HSP70, GPX1, GADD45, QR, mdr1, PGHS, and cyclin D1 changes. A model for KBrO(3)-induced carcinogenicity in the F344 rat mesothelium is proposed, whereby KBrO(3) generates a redox signal that activates p53 and results in transcriptional activation of oxidative stress and repair genes, dysregulation of growth control, and imperfect DNA repair leading to carcinogenesis.
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PMID:Morphologic analysis correlates with gene expression changes in cultured F344 rat mesothelial cells. 1113 43

This work, using RT PCR, studied expression of mRNAs encoding ion transporters, the Na/H antiporter (NHE1), the beta subunit of the Na,K-ATPase pump (ATP1B1), the NaK2Cl symporter (NKCC1), and some proteins unrelated to ion transport: the serum and glucocorticoid dependent kinase (hSGK), beta-actin, a glycolytic enzyme (GAPDH), and regulators of proliferation and apoptosis (p53, Bcl-2) during activation of human lymphocytes with phytohemagglutinin for 4-24 h. Within 24 hours the mRNA levels of NHE1, beta-actin, Bcl-2, and p53 increased by more than 100%, the mRNA levels of ATP1B1, GAPDH, and hSGK, by about 50%, while the mRNA levels of NKCC1 decreased transiently. These results indicate a differential transcriptional control of NHE1, ATP1B1, and NKCC1 following a proliferative stimulus of human lymphocytes.
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PMID:Differential transcription of ion transporters, NHE1, ATP1B1, NKCC1 in human peripheral blood lymphocytes activated to proliferation. 1127 79

Changes in the levels of mRNAs encoding ion transporters (ATP1B1, NHE1, NKCC1), beta-actin, GAPDH, regulators of proliferation and apoptosis (p53, Bcl-2) and kinase hSGK, involved in cell water regulation, were studied using RT PCR in the peripheral human lymphocytes activated with phytohemagglutinin for 4-24 h. The common, "grouped", effect that was found was an increase in the levels of the studied mRNAs after an 8 h activation, sometimes preceded by a delay or slight decrease at the initial stage of 0-4 h. Apart from the common features, some differences were observed in the time courses and amplitudes of the responses of individual mRNAs. The arrangement of the individual mRNA responses in lymphocytes from different donors could differ significantly, thus indicating differential regulation of the studied mRNAs apart from the "grouped" effect. The data obtained confirmed our suggestion that regulation of ion transport at the level of mRNA could be involved in the changes of ion balance at the late stage of lymphocyte activation.
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PMID:[Cell cycle and formation of active form of oxygen in rodent fibroblasts]. 1153 80

A new class of potent apogens (apoptosis-inducing agents) has been identified, consisting of 3-deazaadenosine (DZA), 3-deaza-(+/-)aristeromycin (DZAri) and 1-beta-D-arabinofuranosyl-1H-imidazo[4,5-&cumacr;]pyridine (ara-3-deazaadenine; DZAra-A). They are inhibitors of S-adenosylhomocysteine hydrolase and indirect inhibitors of methylation. Furthermore, they have also been found to form 3-deaza-nucleotide analogs. The DZA analogs, DZA, DZAri, and DZAra-A, induced DNA fragmentation in a dose- and time-dependent manner, reaching a maximum at 250 &mgr;M after 72 h. Cycloheximide at 0.5 &mgr;g/ml completely blocked the DNA fragmentation induced by 250 &mgr;M of each of the analogs. Interestingly, exogenous 100 &mgr;M L-homocysteine thiolactone abrogated the DNA fragmentation caused by DZAri and DZAra-A, but not by DZA. Flow cytometric analysis showed that DZA arrested the cells in the G(2)/M phase, whereas the S phase was arrested by DZAri. Correlated with the effect of DZA was a rapid decrease in the expression of c-myc, whereas nur77 and GAPDH were unaffected. In comparison, there was an elevated expression of IFN-gamma mRNA without apparent change in bax, p53 or GAPDH mRNA after 24 h. After treatment with DZA, there was an elevated expression of NF-kappaB DNA binding activity, which became more pronounced at 24 h. Simultaneously, there was an apparent disappearance of AP-1 activity. Thus, DZA most likely inhibited the RNA synthesis of c-myc, a reduction of which could trigger a cascade of gene transcription leading to apoptosis in L1210 cells. Copyright 1997 S. Karger AG, Basel
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PMID:Apoptosis of L1210 Leukemia Cells Induced by 3-Deazaadenosine Analogs: Differential Expression of c-myc, NF-Kappa B and Molecular Events. 1172 38

We previously demonstrated that RB18A, a member of TRAP220/DRIP205/PBP family, in vivo acted as a cofactor of transcription by differently regulating p53wt transactivating activity on physiological promoters. Using p53-negative cells transfected with different constructs, we herein demonstrated that RB18A down-regulated p53wt-dependent apoptosis. This biological regulation was due to a specific diminution of p53wt protein level, as level of p53mut and GAPDH proteins was not modified. This p53wt diminution was dependent on proteasome activity, as inhibited by MG-132 inhibitor. This specific p53wt degradation was correlated with an increase in expression of MDM2, which promoted p53wt degradation into proteasome. RB18A up-regulated MDM2 expression by activating MDM2 promoter, even in absence of p53wt. Altogether, these data emphasized that RB18A could regulate p53wt function not only by direct interaction between both proteins, but also by up-regulating promoter activity of MDM2, a p53-regulating partner.
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PMID:RB18A regulates p53-dependent apoptosis. 1184 Mar 31

Chronic gestational exposure to ethanol has profound adverse effects on brain development. In this regard, studies using in vitro models of ethanol exposure demonstrated impaired insulin signaling mechanisms associated with increased apoptosis and reduced mitochondrial function in neuronal cells. To determine the relevance of these findings to fetal alcohol syndrome, we examined mechanisms of insulin-stimulated neuronal survival and mitochondrial function using a rat model of chronic gestational exposure to ethanol. In ethanol-exposed pups, the cerebellar hemispheres were hypoplastic and exhibited increased apoptosis. Isolated cerebellar neurons were cultured to selectively evaluate insulin responsiveness. Gestational exposure to ethanol inhibited insulin-stimulated neuronal viability, mitochondrial function, Calcein AM retention (membrane integrity), and GAPDH expression, and increased dihydrorosamine fluorescence (oxidative stress) and pro-apoptosis gene expression (p53, Fas-receptor, and Fas-ligand). In addition, neuronal cultures generated from ethanol-exposed pups had reduced levels of insulin-stimulated Akt, GSK-3beta, and BAD phosphorylation, and increased levels of non-phosphorylated (activated) GSK-3beta and BAD protein expression. The aggregate results suggest that insulin-stimulated central nervous system neuronal survival mechanisms are significantly impaired by chronic gestational exposure to ethanol, and that the abnormalities in insulin signaling mechanisms persist in the early postnatal period, which is critical for brain development.
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PMID:Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. 1208 87

The purpose of this study was to evaluate the extent to which the expression of p53, c-myc, bcl-2, ras genes and chromosomes, along with activity of hTERT, impacts on the malignant transformation of immortalized esophageal epithelial cells. The SHEE cell line was established from an embryonic esophageal epithelial cell induced by transduction of E6E7 genes of human papillomavirus type 18 (HPV18E6E7). In cells of the 85th passage (SHEE85), the malignant transformation of SHEE was confirmed by morphology, cell proliferative index and tumor formation in SCID mice. C-myc, p53, bcl-2 and ras genes were assayed by the multi-PCR method with house-keeping gene GAPDH as control. The modal number of chromosomes was analyzed and its expression of subunit of telomerase, hTERT, was assessed by RT-PCR. Expression of HPV18E6E7 was assayed by Western blotting. The results showed that cells of SHEE85 were atypical and exhibited proliferative status with a proliferation index of 45.70%. Tumors formed in SCID mice with invasion of adjacent tissue. The karyotype belonged to hypotriploid and displayed expression of hTERT. C-myc, k-ras, bcl-2 and p53 (expression of phosphoprotein) were positive in SHEE85. Expression of HPV18E6E7 was positive. Taken together, SHEE85 cells were in fully malignant transformation and their molecular mechanism involved the expression of cellular genes, such as p53, bcl-2, c-myc and ras, and aberrance of chromosomes. It is probable that all of these changes were related with HPV18E6E7.
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PMID:Cytogenetic and molecular genetic changes in malignant transformation of immortalized esophageal epithelial cells. 1285 21


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