Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Feed restriction and once-daily milking (ODM) reduce milk yield in dairy cows and the amount of glucose taken up by the mammary gland. The modulation of mammary glucose uptake may be the consequence of modifications to glucose transport, capacity for lactose synthesis, and cell death in mammary epithelial cells (MEC). The aim was to demonstrate the usefulness of a new method to purify MEC from milk somatic cells and to examine the effects of feed restriction and ODM on mammary transcripts. Five Holstein cows were subjected to a 2 x 2 factorial arrangement of 2 milking frequencies and 2 feeding levels, during which the cows were milked once or twice daily while fed a diet providing either 98 or 70% of requirements. The cows were equipped to study net mammary balance of glucose. On d 7 of each experimental week, milk and lactose yields and mammary glucose uptake were measured. Cells were isolated from fresh milk by centrifugation to generate total milk cell samples. Mammary epithelial cells were separated from total milk cells by using magnetic beads associated with anticytokeratin 8 antibodies. Total RNA was extracted from both total milk cells and purified MEC samples. Real-time reverse transcription PCR was performed to determine mRNA levels in purified MEC under feed restriction and under ODM. Purified MEC samples revealed higher total RNA quality (RNA integrity number = 8) and were better suited to the measurement of mammary transcripts than total milk cell samples (RNA integrity number = 4). Significant correlations were obtained between mRNA levels and net glucose balance data (0.465 < r < 0.680), demonstrating the validity of results obtained by using purified MEC. Feed restriction induced a significant reduction (by half) in type 1 glucose transporter mRNA levels without any effect on alpha-lactalbumin (alpha-LA), galactosyltransferase, kappa-casein, bcl2, or bax mRNA levels. When compared with twice daily milking, ODM reduced kappa-casein (-86%) and alphaLA (-73%) mRNA levels and up-regulated bax and bcl2 mRNA levels (7- and 9-fold). The results suggest that the regulation of glucose uptake and milk yield is dependent on the transcription of glucose transporters under feed restriction and on the transcription of alphaLA under ODM. Further studies are required to con-firm the suggested onset of cell death after 7 d of ODM.
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PMID:Milking and feed restriction regulate transcripts of mammary epithelial cells purified from milk. 1829 54

Lymphocytes require glucose uptake and metabolism for normal survival and function. The signals that regulate the expression and localization of glucose transporter 1 (Glut1) to allow glucose uptake in T cells are now beginning to be understood. Resting T cells require extracellular signals, such as cytokines, hormones, and growth factors, or low-level TCR stimulation to take up adequate glucose to maintain housekeeping functions. In the absence of extrinsic signals, resting T cells internalize and degrade Glut1 and cannot maintain viability. Activated T cells have dramatically increased metabolic requirements to support the energy and biosynthetic needs necessary for growth, proliferation, and effector function. In particular, glucose metabolism and aerobic glycolysis fuel this demand. Therefore, activation of T cells causes a large increase in Glut1 expression and surface localization. If glucose uptake is limited, glycolytic flux decreases to a level that no longer sustains viability, and proapoptotic Bcl-2 family members become activated, promoting cell death. However, excessive glucose uptake can promote hyperactive immune responses and possible immune pathology. Tight regulation of glucose uptake is required to maintain immune homeostasis, and understanding of these metabolic pathways may lead to therapeutic strategies to target some forms of cancer or autoimmunity.
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PMID:Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. 1857 16

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there are few therapeutic regimens that influence the underlying pathogenic phenotypes. However, of the currently available therapies, exercise training is considered to be one of the best candidates for amelioration of the pathological phenotypes of AD. Therefore, we directly investigated exercise training to determine whether it was able to ameliorate the molecular pathogenic phenotypes in the brain using a neuron-specific enolase (NSE)/Swedish mutation of amyloid precursor protein (APPsw) transgenic (Tg) mice as a novel AD model. To accomplish this, Non-Tg and NSE/ APPsw Tg mice were subjected to exercise on a treadmill for 16 weeks, after which their brains were evaluated to determine whether any changes in the pathological phenotype-related factors had occurred. The results indicated (i) that amyloid beta-42 (Abeta-42) peptides were significantly decreased in the NSE/APPsw Tg mice following exercise training; (ii) that exercise training inhibited the apoptotic biochemical cascades, including cytochrome c, caspase-9, caspase-3 and Bax; (iii) that the glucose transporter-1 (GLUT-1) and brain-derived neurotrophic factor (BDNF) proteins induced by exercise training protected the neurons from injury by inducing the concomitant expression of genes that encode proteins such as superoxide dismutase-1 (SOD-1), catalase and Bcl-2, which suppress oxidative stress and excitotoxic injury; (iv) that heat-shock protein-70 (HSP-70) and glucose-regulated protein-78 (GRP-78) were significantly increased in the exercise (EXE) group when compared to the sedentary (SED) group, and that these proteins may benefit the brain by making it more resistant to stress-induced neuron cell damage; (v) and that exercise training contributed to the restoration of normal levels of serum total cholesterol, insulin and glucose. Taken together, these results suggest that exercise training represents a practical therapeutic strategy for human subjects suffering from AD. Moreover, this training has the potential for use in new therapeutic strategies for the treatment of other chronic disease including diabetes, cardiovascular and Parkinson's disease.
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PMID:Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model. 1881 61

Growth factor stimulation and oncogenic transformation lead to increased glucose metabolism that may provide resistance to cell death. We have previously demonstrated that elevated glucose metabolism characteristic of stimulated or cancerous cells can stabilize the anti-apoptotic Bcl-2 family protein Mcl-1 through inhibition of GSK-3. Here we show that the pro-apoptotic Bcl-2 family protein, Puma, is also metabolically regulated. Growth factor deprivation led to the loss of glucose uptake and induction of Puma. Maintenance of glucose uptake after growth factor withdrawal by expression of the glucose transporter, Glut1, however, suppressed Puma up-regulation and attenuated growth factor withdrawal-induced activation of Bax, DNA fragmentation, and cell death. Conversely, glucose deprivation led to Puma induction even in the presence of growth factor. This regulation of Puma expression was a central component in cell death as a consequence of growth factor or glucose deprivation because Puma deficiency suppressed both of these cell death pathways. Puma induction in growth factor or glucose withdrawal was dependent on p53 in cell lines and in activated primary T lymphocytes because p53 deficiency suppressed Puma induction and delayed Bax and caspase activation, DNA fragmentation, and loss of clonogenic survival. Importantly, although p53 levels did not change or were slightly reduced, p53 activity was suppressed by elevated glucose metabolism to inhibit Puma induction after growth factor withdrawal. These data show that p53 is metabolically regulated and that glucose metabolism initiates a signaling mechanism to inhibit p53 activation and suppress Puma induction, thus promoting an anti-apoptotic balance to Bcl-2 family protein expression that supports cell survival.
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PMID:Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation. 1899 Jun 90

Phloretin (Ph), a natural product found in apples and pears with glucose transporter (GLUT) inhibitory activity, exerts antitumor effects. However, little is known about its effects on human liver cancer. The purpose of this study is to test the cytotoxic effects of Ph on HepG2 cells and to identify the underlying molecular pathways. Human hepatocellular carcinoma specimens and HepG2 show a high level of GLUT2 transporter activity in the cell membrane. Real-time PCR and MTT assays demonstrate that Ph-induced cytotoxicity correlates with the expression of GLUT2. Flow cytometry and DNA fragmentation studies show that 200 microM Ph induces apoptosis in HepG2, which was reversed by glucose pretreatment. GLUT2 siRNA knockdown induced HepG2 apoptosis, which was not reversed by glucose. Western blot analysis demonstrates that both intrinsic and extrinsic apoptotic pathways in addition to Akt and Bcl-2 family signaling pathways are involved in Ph-induced cell death in HepG2 cells. Furthermore, using flow cytometry analysis, a mitochondrial membrane potential assay and Western blot analysis, we show that cytochalasin B, a glucose transport inhibitor, enhances the Ph-induced apoptotic effect on HepG2 cells, which was reversed by pretreatment with glucose. Furthermore, we found significant antitumor effects in vivo by administering Ph at 10 mg/kg intraperitoneally to severe combined immune deficiency mice carrying a HepG2 xenograft. A microPET study in the HepG2 tumor-bearing mice showed a 10-fold decrease in (18)F-FDG uptake in Ph-treated tumors compared to controls. Taken together, these results suggest that Ph-induced apoptosis in HepG2 cells involves inhibition of GLUT2 glucose transport mechanisms.
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PMID:In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. 1912 83

Uptake by macrophages forms an important part of the mode of action of particulate adjuvants such as oil-in-water emulsions and alum. We have found previously that such adjuvants promote macrophage survival and suggested that this response may contribute to their efficacy. To explore this adjuvant activity further, we have investigated whether oil-in-water emulsion stimulates glucose uptake in macrophages and whether such uptake is relevant to the promotion of survival. We found that oil-in-water emulsion stimulated glucose uptake in a biphasic manner. The first acute phase was independent of mRNA and protein synthesis but appeared to require PI3K activity. In contrast, the second chronic phase was dependent on mRNA and protein synthesis. Importantly, the second phase of glucose uptake required MEK1/2 as well as PI3K activity, indicating that the MEK1/2 pathway can also contribute to cellular glucose uptake. The increased glucose transporter 1 expression during the second phase and long-term survival also appeared to be dependent on PI3K and MEK1/2 signaling pathways. Metabolism of the glucose was required for the emulsion-stimulated survival as well as the increase of prosurvival Bcl-2 transcript levels and maintenance of Bcl-2 protein expression. As transgenic overexpression of Bcl-2 enhances the survival of macrophages in the absence of growth factor, the glycolytic control of Bcl-2 levels may play a central role in emulsion-stimulated macrophage survival. Enhanced glucose uptake by macrophages may therefore be critical to the action of particulate adjuvants.
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PMID:Glycolytic control of adjuvant-induced macrophage survival: role of PI3K, MEK1/2, and Bcl-2. 1927 84

High [(18)F]-2-fluorodeoxyglucose (FDG)-uptake of oral squamous cell carcinoma (OSCC), assessed by pretreatment positron emission tomography (PET), has indicated poor survival of patients. In this study, we sought to elucidate the underlying pathological and biological mechanisms of the close correlation in OSCC between high FDG-uptake and poor survival. Twenty-three patients who underwent both pretreatment FDG-PET and radical surgery were evaluated. We calculated the maximum standardized uptake value (SUVmax) as FDG-uptake. Tumor thickness and depth of invasion were quantitatively measured. Pathological specimens were immunohistochemically stained with antibodies to glucose transporter-1, E-cadherin, beta-catenin, vascular endothelial growth factor (VEGF), VEGF-C and Bcl-2, and their expressions were densitometrically assessed. SUVmax was significantly correlated with both tumor thickness and depth of invasion in simple regression analysis. Patients with SUVmax12 exhibited significantly shorter 3-year overall survival than patients with SUVmax < 12. Tumors with SUVmax > or =12 showed significantly greater tumor thickness, depth of invasion and average Bcl-2 intensity than those with SUVmax<12. Furthermore, tumor thickness> or =11.4mm, depth of invasion> or =11.8mm and average Bcl-2 intensity > or =50% were significantly correlated with poor survival. These results suggest that SUVmax in OSCC is significantly correlated with pathological features, and that it is both a non-invasive and useful parameter for predicting patients' prognosis.
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PMID:Tumor thickness, depth of invasion, and Bcl-2 expression are correlated with FDG-uptake in oral squamous cell carcinomas. 1945 11

In chronic inflammatory lesions macrophages are abundant and adapt to the low oxygen concentrations often present there. In low oxygen some cell types die by apoptosis, as reported for macrophage cell lines, while others survive better as they shift their metabolism to anaerobic glycolysis. It was found here that hypoxia prolongs the survival of murine bone marrow-derived macrophages, either in the absence or presence of low CSF-1 (M-CSF) concentrations. Although Akt activity increased in bone marrow-derived macrophages in the low oxygen conditions, the levels of both anti- and proapoptotic Bcl-2 family members decreased. Glycolysis was enhanced as judged by increased glucose uptake, glucose transporter expression, lactate dehydrogenase mRNA expression, and lactate secretion. Human monocytes responded similarly to low oxygen, and a number of genes associated with glycolysis were shown by microarray analysis and quantitative PCR to be up-regulated. Interestingly, human monocyte-derived macrophages showed evidence of enhanced glycolysis even under aerobic conditions. It is proposed that certain monocyte/macrophage populations survive better under conditions of low oxygen, thereby contributing to their increased numbers at sites of chronic inflammation and tumors; it is also proposed that as macrophages differentiate from monocytes they begin to adopt a glycolytic metabolism allowing them to adapt readily when exposed to low oxygen conditions.
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PMID:Hypoxia prolongs monocyte/macrophage survival and enhanced glycolysis is associated with their maturation under aerobic conditions. 1949 22

Activation of the transcription factor hypoxia-inducible factor (HIF)-1 allows solid tumors to thrive under conditions of metabolic stress. Because HIF-1 is switched off by hydroxylation reactions that require ascorbate, inadequate intracellular ascorbate levels could contribute to HIF-1 overactivation. In this study, we investigated whether the ascorbate content of human endometrial tumors [known to be driven by HIF-1 and vascular endothelial growth factor (VEGF)] influenced HIF-1 activity and tumor pathology. We measured protein levels of HIF-1alpha and three downstream gene products [glucose transporter 1 (GLUT-1), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and VEGF], as well as the ascorbate content of tumor and patient-matched normal endometrial tissue samples. HIF-1alpha and its downstream gene products were upregulated in tumor tissue, with the highest levels being present in high-grade tumors. High-grade tumors also had reduced capacity to accumulate ascorbate compared with normal tissue; however, all grades contained tumors with low ascorbate content. Tumors with the highest HIF-1alpha protein content were ascorbate deficient. Low ascorbate levels were also associated with elevated VEGF, GLUT-1, and BNIP3 protein levels and with increased tumor size, and there was a significant association between low tissue ascorbate levels and increased activation of the HIF-1 pathway (P = 0.007). In contrast, tumors with high ascorbate levels had lesser levels of HIF-1 activation. This study shows for the first time a likely in vivo relationship between ascorbate and HIF-1, with low tumor tissue ascorbate levels being associated with high HIF-1 activation and tumor growth.
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PMID:Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. 2057 Aug 89


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