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)

Our group has developed more than 600 DNA markers to build a map of the canine genome. Of these markers, 125 correspond to genes (anchor loci). Here we report the first six autosomal genes assigned to canine chromosomes by fluorescence in situ hybridization (FISH), using cosmid DNA: adenine phosphoribosyl transferase on Chromosome (Chr) 3; creatine kinase muscle type on Chr 4; pyruvate kinase liver and red blood cell type on Chr 2; and colony-stimulating factor-1 receptor, glucose transporter protein-2, and tumor protein p53 on Chr 5. These assignments are based on the karyotype proposed by Stone and associates (Genome 34, 407, 1991) using high-resolution techniques. In addition, we have assigned the Menkes gene to the X Chr of the dog.
 ...
PMID:Chromosomal assignment of seven genes on canine chromosomes by fluorescence in situ hybridization. 866 96

Hypoxia causes a large array of adaptive and physiological responses in all cells including cardiac myocytes. In order to elucidate the molecular effects of increased glucose flux on hypoxic cardiac myocytes we focused on the basic helix-loop-helix transcription factor, hypoxia inducible factor 1 alpha (HIF-1alpha), which is rapidly upregulated in hypoxic cells and elicits a number of responses including augmentation of glucose uptake. Primary cultures of neonatal rat cardiac myocytes as well as embryonic rat heart-derived myogenic H9c2 cells demonstrated a significant upregulation of HIF-1alpha when subjected to hypoxia of 6-8h in the absence of glucose. Re-addition of extracellular glucose to the medium resulted in a decrease of HIF-1alpha levels by almost 50%. This glucose effect was blocked by addition of glycolytic inhibitors. In addition, glucose uptake and glycolysis resulted in substantial decreased levels of p53, which is regulated by HIF-1alpha. Adenoviral infection of cultures of cardiac myocytes with the facilitative glucose transporter, GLUT1 followed by hypoxia of 24h also resulted in a significant reduction in the protein expression of HIF-1alpha compared to control vector-infected cultures. GLUT1 infected cultures also demonstrated fewer apoptotic cells and a reduction in the release of cytochrome c after hypoxia. Inhibition of the ubiquitin-proteasomal pathway by a variety of 26S proteasomal inhibitors increased HIF-1alpha to similar levels under both normoxic and hypoxic conditions and in the presence or absence of glucose. This result suggested that glucose induces HIF-1alpha degradation via a proteasomal pathway. This conclusion was substantiated by immunoprecipitation experiments of total cell extracts, which demonstrated an increase of ubiquitinated HIF-1alpha relative to total HIF-1alpha in the presence of glucose during hypoxia. Thus, glucose as well as GLUT1 overexpression diminishes hypoxia-induced HIF-1alpha protein via an ubiquitin-proteasomal pathway in hypoxic cardiac myocytes. This represents a novel feedback mechanism that may play an important role in adaptation of cardiac myocytes to hypoxia and ischemia.
 ...
PMID:Glucose uptake and adenoviral mediated GLUT1 infection decrease hypoxia-induced HIF-1alpha levels in cardiac myocytes. 1223 75

Tumorigenesis is associated with enhanced cellular glucose uptake and increased metabolism. Because the p53 tumor suppressor is mutated in a large number of cancers, we evaluated whether p53 regulates expression of the GLUT1 and GLUT4 glucose transporter genes. Transient cotransfection of osteosarcoma-derived SaOS-2 cells, rhabdomyosarcoma-derived RD cells, and C2C12 myotubes with GLUT1-P-Luc or GLUT4-P-Luc promoter-reporter constructs and wild-type p53 expression vectors dose dependently decreased both GLUT1 and GLUT4 promoter activity to approximately 50% of their basal levels. PG(13)-Luc activity, which was used as a positive control for functional p53 expression, was increased up to approximately 250-fold by coexpression of wild-type p53. The inhibitory effect of wild-type p53 was greatly reduced or abolished when cells were transfected with p53 with mutations in amino acids 143, 248, or 273. A region spanning -66/+163 bp of the GLUT4 promoter was both necessary and sufficient to mediate the inhibitory effects of p53. Furthermore, in vitro translated p53 protein was found to bind directly to two sequences in that region. p53-DNA binding was completely abolished by excess unlabeled probe but not by nonspecific DNA and was super-shifted by the addition of an anti-p53 antibody. Taken together, our data strongly suggest that wild-type p53 represses GLUT1 and GLUT4 gene transcription in a tissue-specific manner. Mutations within the DNA-binding domain of p53, which are usually associated with malignancy, were found to impair the repressive effect of p53 on transcriptional activity of the GLUT1 and GLUT4 gene promoters, thereby resulting in increased glucose metabolism and cell energy supply. This, in turn, would be predicted to facilitate tumor growth.
 ...
PMID:The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. 1505 20

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.
 ...
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

Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1alpha. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O(2) at 37 degrees C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1alpha was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1alpha and p53 was also examined. An elevated expression of HIF-1alpha, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1alpha was followed by an increase in the association of HIF-1alpha with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1alpha and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1alpha-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1alpha phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.
 ...
PMID:Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes. 1672 20

In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)-1alpha in breast cancer, especially the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition for transcriptional coactivators such as p300. The aim of this study was therefore to explore the role of p53 and p300 in relation to overexpression of HIF-1alpha and activation of HIF-1 downstream genes in invasive breast cancer. p300 immunohistochemistry was performed in a group of 183 early-stage invasive breast cancers, and related to p53 accumulation, overexpression of HIF-1alpha, and several HIF-1 downstream genes. p300 was expressed in varying degrees in 84% of invasive breast cancers. p300 staining intensity correlated positively with HIF-1alpha expression (P = .04), p53 accumulation (P = .001), and overexpression of glucose transporter 1 (GLUT-1) (P < .001), a glucose transporter downstream target gene of HIF-1. GLUT-1 levels were significantly associated with p300 in HIF-1alpha positive patients (P = .02). p53 accumulation significantly positively correlated with carbonic anhydrase IX (CAIX)/GLUT-1 coexpression in HIF-1alpha-positive patients (P = .007). p53 accumulation/high p300 levels, the most favorable situation for HIF-1 downstream activation, were significantly associated with GLUT-1 overexpression (P = .01) and coexpression of CAIX/GLUT-1 (P = .03), compared with low p53/low p300 levels, the most unfavorable situation for HIF-1 downstream activation. p300 is a cofactor highly associated with p53 accumulation and HIF-1alpha levels in invasive breast cancer. Furthermore, low levels of p300 may explain absence of downstream effects in HIF-1alpha-overexpressing cancers, an effect that seems to be enhanced by wild-type levels of p53. This underlines the importance of p300 levels and p53 accumulation in the HIF-1-regulated response toward hypoxia.
 ...
PMID:p300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer. 1686 72

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.
 ...
PMID:Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. 1704 58

The separation of benign reactive mesothelium (RM) from malignant mesothelial proliferation can be a major challenge. A number of markers have been proposed, including epithelial membrane antigen, p53 protein, and P-glycoprotein. To date, however, no immunohistochemical marker that allows unequivocal discrimination of RM from malignant pleural mesothelioma (MPM) has been available. A family of glucose transporter isoforms (GLUT), of which GLUT-1 is a member, facilitate the entry of glucose into cells. GLUT-1 is largely undetectable by immunohistochemistry in normal epithelial tissues and benign tumors, but is expressed in a variety of malignancies. Thus, the expression of GLUT-1 appears to be a potential marker of malignant transformation. Recently, in fact, some studies have shown that GLUT-1 expression is useful for distinguishing benign from malignant lesions. The purpose of the present study was to evaluate the diagnostic utility of GLUT-1 expression for diagnostic differentiation between RM and MPM. Immunohistochemical staining for GLUT-1 was performed in 40 cases of RM, 48 cases of MPM, and 58 cases of lung carcinoma. Immunohistochemical GLUT-1 expression was seen in 40 of 40 (100%) MPMs, and in all cases the expression was demonstrated by linear plasma membrane staining, sometimes with cytoplasmic staining in addition. GLUT-1 expression was also observed in 56 out of 58 (96.5%) lung carcinomas. On the other hand, no RM cases were positive for GLUT-1. GLUT-1 is a sensitive and specific immunohistochemical marker enabling differential diagnosis of RM from MPM, whereas it cannot discriminate MPM from lung carcinoma.
 ...
PMID:Immunohistochemical detection of GLUT-1 can discriminate between reactive mesothelium and malignant mesothelioma. 1719 90

The aim of the study was to explore whether expression of proliferation and hypoxia-related proteins differs in the central parts and the invasive front in endometrial carcinomas. Proliferation-associated proteins Ki67 and cyclin A; cell cycle regulators p16, p21, p53, cyclin D1, cyclin E, and cdk2; and hypoxia-inducible factor 1alpha and its downstream factors glucose transporter 1, carbonic anhydrase IX, and vascular endothelial growth factor were immunohistochemically stained in paraffin-embedded specimens from endometrioid (n = 33), mucinous (n = 1), and serous (n = 5) endometrial carcinomas. The percentages of positive cells at the invasive front and central tumor parts were scored and compared. Ki67 (P < .001), cyclin E (P = .018), p16 (P = .003), and cdk2 (.001) were expressed higher at the invasive front than centrally (Wilcoxon signed ranks test). Higher expression of these antigens at the invasive front was seen in 31 of 38 cases for Ki67, in 16 of 39 cases for cyclin E, in 15 of 39 cases for cdk2, and in 11 of 39 cases for p16. The other cell cycle proteins and the hypoxia-related factors did not show significant differences in expression between the central parts and the invasive front. Endometrial carcinomas clearly show an invasive front that is characterized by higher proliferation and progressive derailment of the cell cycle regulators cyclin E, p16, and cdk2, but not by an increased hypoxic response.
 ...
PMID:The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators. 1749 Jul 24

The expression of glucose transporter protein 1 (GLUT1) in malignant tumors is increased due to the higher metabolic needs of the proliferating cell populations. Aberrant GLUT1 expression is exhibited in a wide spectrum of epithelial malignancies and their precursors, which occur with low frequency and intensity; aberrant GLUT1 expression does not occur in normal epithelial cells. The expression of GLUT1 in tumors of the ampulla of Vater was evaluated on immunohistochemistry, and the relationships of GLUT1 expression to histological parameters and p53 expression were analyzed. Twenty-one (58.3%) of 36 adenocarcinomas and three (17.6%) of 17 adenomas had GLUT1 immunoreactivity. None of the regenerating or normal epithelia had any immunoreactivity. No significant relationships were found between GLUT1 expression and histological parameters or p53 expression. It was found that histological subtypes originated from different epithelium were strongly related to different macroscopic types. In the ampulla of Vater, GLUT1 expression was associated with malignant change, and might be a useful marker of malignancy.
 ...
PMID:Significance of GLUT1 expression in adenocarcinoma and adenoma of the ampulla of Vater. 1832 16


1 2 3 4 5 6 Next >>