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: EC:2.7.11.11 (AMPK)
12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Senescence is a potential tumor-suppressing mechanism and a commonly used model of cellular aging. One current hypothesis to explain senescence, based in part on the correlation of oxygen with senescence, postulates that it is caused by oxidative damage from reactive oxygen species (ROS). Here, we further test this theory by determining the mechanisms of hyperoxia-induced senescence. Exposure to 70% O(2) led to stress-induced, telomere-independent senescence. Although hyperoxia elevated mitochondrial ROS production, overexpression of antioxidant proteins was not sufficient to prevent hyperoxia-induced senescence. Hyperoxia activated AMPK; however, overexpression of a kinase-dead mutant of LKB1, which prevented AMPK activation, did not prevent hyperoxia-induced senescence. Knocking down p21 via shRNA, or suppression of the p16/pRb pathway by either BMI1 or HPV16-E7 overexpression, was also insufficient to prevent hyperoxia-induced senescence. However, suppressing p53 function resulted in partial rescue from senescence, suggesting that hyperoxia-induced senescence involves p53. Suppressing both the p53 and pRb pathways resulted in almost complete protection, indicating that both pathways cooperate in hyperoxia-induced senescence. Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia.
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PMID:Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS. 1894 82

Reactive oxygen species (ROS) play an important role in cellular function via the activation of signaling cascades. ROS have been shown to affect mitochondrial biogenesis, morphology, and function. Their beneficial effects are likely mediated via the upregulation of transcriptional regulators such as peroxisome proliferator-activated receptor-gamma coactivator-1 protein-alpha (PGC-1alpha). However, the ROS signals that regulate PGC-1alpha transcription in skeletal muscle are not understood. Here we examined the effect of H2O2 on the regulation of PGC-1alpha expression, and its relationship to AMPK activation. We demonstrate that 24 h of exogenous H2O2 treatment increased PGC-1alpha promoter activity and mRNA expression. Both effects were blocked with the addition of N-acetylcysteine, a ROS scavenger. These effects were mediated, in part, via upstream stimulatory factor-1/Ebox DNA binding and involved 1) interactions with downstream sequences and 2) the activation of AMPK. Elevated ROS led to the activation of AMPK, likely via a decline in ATP levels. The activation of AMPK using 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside increased PGC-1alpha promoter activity and mRNA levels but reduced ROS production. Thus the net effect of AMPK activation on PGC-1alpha expression was a result of increased transcriptional activation, counterbalanced by reduced ROS production. The effects of H2O2 on PGC-1alpha expression differed depending on the level of ROS within the cell. Low levels of ROS result in reduced PGC-1alpha mRNA in the absence of an effect on PGC-1alpha promoter activation. In contrast, elevated levels of H2O2 induce PGC-1alpha transcription indirectly, via AMPK activation. These data identify unique interactions between ROS and AMPK activation on the expression of PGC-1alpha in muscle cells.
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PMID:Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. 1900 63

Population studies have revealed that treatment with the antidiabetic drug metformin significantly associates with reduced breast cancer risk. Animal studies have shown that metformin suppresses the development of mammary carcinomas in transgenic female mice carrying a HER2 oncogene, but not that of spontaneous tumors. We herein demonstrate that HER2 oncoprotein itself may represent a key cellular target involved in the anti-breast cancer actions of metformin. First, ectopical overexpression of HER2 oncogene significantly enhances metformin-induced breast cancer cell growth inhibition. Second, metformin treatment drastically downregulates HER2 protein levels (up to 85% reduction) in a dose- and time-dependent manner. Metformin-induced inhibition of HER2 take places regardless the molecular mechanism contributing to HER2 overexpression (i.e., human HER2 cDNA exogenously driven by a viral promoter and naturally occurring endogenous HER2 gene amplification). Mechanistically, metformin-induced suppression of HER2 overexpression appears to occur via direct (AMPK-independent) inhibition of p70S6K1 activity. Compound C- and small interference RNA (siRNA)-induced blockade of AMPK activity/expression fail to prevent the anti-HER2 effect of metformin while AMPK hyperactivation following exposure to the AMP analog AICAR is not sufficient to downregulate HER2 expression. HER2-positive breast cancer cells transfected with p70S6K1 siRNA become completely refractory to metformin-induced HER2 suppression. Of note, co-incubation with agents that block reactive oxygen species (ROS) production (e.g., N-acetylcysteine) dramatically enhanced the ability of metformin to decrease HER2 expression. From the perspective of chemoprevention, these findings altogether suggest that metformin might exert a protective mostly confined to the HER2-positive breast cancer subtype. From the perspective of intervention, the presence/absence of molecular hallmarks such as HER2 overexpression and/or p70S6K1 hyperactivation might dictate alternative responses in metformin-based treatment of early breast cancer. The importance of mTOR/p70S6K1-sensed ROS status at mediating the anti-oncogenic effects of metformin might represent a previously unrecognized linkage molecularly connecting its anti-aging and anti-cancer actions.
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PMID:The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. 1910 26

Chondrocytes in the growth plate and articular cartilage and osteocytes subsumed in Haversian bone exist in environmental niches that are characterized by a limited oxygen supply. In these tissues, cells display a hitherto unrecognized state in which there is evidence of autophagy. The autophagic condition serves to promote cell survival. When the response is triggered, the cell cannibalizes itself to generate energy; if extended, then it can activate Type II apoptosis. We opine that survival is dependent on niche conditions and regulated by crosstalk between mTOR, AMPK and HIF-1 and HIF-2. Recent studies suggest that HIF-2 is a potent regulator of chondrocyte autophagy and that this protein acts as a brake to the stimulatory function of HIF-1. Accordingly, the oxemic state of the tissue, its nutrient supply as well as the energetic state of the cells regulates autophagic flux. From a clinical viewpoint, it may be possible to enhance skeletal cell survival through drugs that modulate the autophagic state and prevent the induction of apoptosis.
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PMID:Autophagy in mineralizing tissues: microenvironmental perspectives. 1917 14

Skeletal muscle is the major store and consumer of fatty acids and glucose. Glucose enters muscle through glucose transporter 4 (GLUT4). Upon insufficient oxygen availability or energy compromise, aerobic metabolism of glucose and fatty aids cannot proceed, and muscle cells rely on anaerobic metabolism of glucose to restore cellular energy status. An increase in glucose uptake into muscle is a key response to stimuli requiring rapid energy supply. This chapter analyses the mechanisms of the adaptive regulation of glucose transport that rescue muscle cells from mitochondrial uncoupling. Under these conditions, the initial drop in ATP recovers rapidly, through a compensatory increase in glucose uptake. This adaptive response involves AMPK activation by the initial ATP drop, which elevates cell surface GLUT4 and glucose uptake. The gain in surface GLUT4 involves different signals and routes of intracellular traffic compared with those engaged by insulin. The hormone increases GLUT4 exocytosis through phosphatidylinositol 3-kinase and Akt, whereas energy stress retards GLUT4 endocytosis through AMPK and calcium inputs. Given that energy stress is a component of muscle contraction, and that contraction activates AMPK and raises cytosolic calcium, we hypothesize that the increase in glucose uptake during contraction may also involve a reduction in GLUT4 endocytosis.
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PMID:Regulation of glucose transporter 4 traffic by energy deprivation from mitochondrial compromise. 1924 52

Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38alpha activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38alpha sustains the expression of HIF1alpha target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38alpha triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38alpha inhibits CRC growth in xenografted nude mice and azoxymethane-treated Apc(Min) mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38alpha affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.
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PMID:p38alpha blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1alpha- to FoxO-dependent transcription. 1934 39

Tumor cells survive under conditions of nutrient deprivation by mechanisms that are not fully understood. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and blocks oxidative stress-induced death. The present studies show that MUC1 inhibits the induction of necrosis in response to the deprivation of glucose. MUC1 suppressed glucose deprivation-induced increases in reactive oxygen species (ROS) and thereby depletion of ATP and cell death. Cells respond to oxidative stress and energy depletion with the induction of autophagy. Our results demonstrate that MUC1 blocks depletion of ATP and sustains growth of glucose-deprived cells by a mechanism sensitive to the autophagy inhibitor, 3-methyladenine. Silencing expression of ATG7, a protein essential for the formation of autophagic vacuoles, also attenuated the MUC1-sustained increases in ATP and growth in response to glucose deprivation. Moreover, we found that MUC1 stimulates AMPK activation and thereby promotes lysosomal turnover of LC3-II, a marker of starvation-induced autophagic activity. These results indicate that MUC1 suppresses glucose deprivation-induced increases in ROS and thereby promotes ATP production and survival. The findings also indicate that the overexpression of MUC1 as found in human cancers could provide a survival advantage in microenvironments with low glucose levels.
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PMID:MUC1 oncoprotein promotes autophagy in a survival response to glucose deprivation. 1942 88

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKalpha1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKalpha1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, gamma-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKalpha1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKalpha1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKalpha1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.
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PMID:AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. 1944 39

The expression of oncogenic ras in normal human cells quickly induces an aberrant proliferation response that later is curtailed by a cell cycle arrest known as cellular senescence. Here, we show that cells expressing oncogenic ras display an increase in the mitochondrial mass, the mitochondrial DNA, and the mitochondrial production of reactive oxygen species (ROS) prior to the senescent cell cycle arrest. By the time the cells entered senescence, dysfunctional mitochondria accumulated around the nucleus. The mitochondrial dysfunction was accompanied by oxidative DNA damage, a drop in ATP levels, and the activation of AMPK. The increase in mitochondrial mass and ROS in response to oncogenic ras depended on intact p53 and Rb tumor suppression pathways. In addition, direct interference with mitochondrial functions by inhibiting the expression of the Rieske iron sulfur protein of complex III or the use of pharmacological inhibitors of the electron transport chain and oxidative phosphorylation was sufficient to trigger senescence. Taking these results together, this work suggests that mitochondrial dysfunction is an effector pathway of oncogene-induced senescence.
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PMID:Mitochondrial dysfunction contributes to oncogene-induced senescence. 1952 27

Avian uncoupling protein (avUCP) is orthologous to UCP3, which is suggested to be involved in fatty acid metabolism and to limit the mitochondrial production of reactive oxygen species in mammals. In the chicken, the role and regulation of avUCP remain to be clarified. The aim of this study was to explore the control of avUCP expression by the beta-adrenergic system, known to be involved in avian thermoregulation and lipid utilization, and in UCP expression in mammals. Therefore, we measured the expression of avUCP mRNA and protein in the Pectoralis major muscle of chickens injected with the beta(2) agonist isoproterenol, and we investigated the potential pathways involved in the regulation of avUCP mRNA expression. Avian UCP mRNA expression was increased 7-fold 4h after isoproterenol injection, leading to a tendency to a 40% increase in avUCP protein 24h post-injection. This increase was preceded, 30 min after isoproterenol injection, by changes in the chicken thyroid status and in the muscular expression of PPARalpha, PPARbeta/delta, and PPARgamma coactivator-1alpha (PGC-1alpha). Moreover, the analysis of the avUCP promoter sequence suggested potential binding sites for PPARs and for thyroid hormone receptors. We also detected the activation of AMP-activated protein kinase, which has recently been reported to be involved in UCP3 regulation in mammals. This study presents for the first time evidence of beta-adrenergic control on avUCP messenger expression in chicken muscle and suggests the potential involvement of AMPK and several transcription factors in this regulation.
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PMID:The beta-adrenergic system is involved in the regulation of the expression of avian uncoupling protein in the chicken. 1978 2


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