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)

AM251, a cannabinoid antagonist, has various biological activities. In this study, we found that AM251 suppressed the viability of hepatoma HepG2 cells and also increased phosphorylation of JNK (c-jun N-terminal kinase) and ATF3 (activating transcription factor 3). In addition, AM251 phosphorylated AMPK (AMP-activated protein kinase) in a time and dose-dependent manner. Inhibition of AMPK blocked AM251-induced JNK/ATF3 phosphorylation. Expression of AMPK or treatment with AICAR (5-aminoimidazole-4-carboxy-amide-1-d-ribofuranoside), an AMPK activator, activated the JNK/ATF3 pathways. Together, these results suggest that AM251 may have anti-tumor effects in hepatoma through activation of the AMPK-JNK-ATF3 signal pathway.
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PMID:AM251 suppresses the viability of HepG2 cells through the AMPK (AMP-activated protein kinase)-JNK (c-Jun N-terminal kinase)-ATF3 (activating transcription factor 3) pathway. 1840 47

AMP-activated protein kinase, AMPK, is responsible for regulation of exercise-induced GLUT4 gene expression in skeletal muscle. But the molecular mechanisms for this regulation and key protein in this signaling pathway are obscure. There has been growing recognition that histone acetylation probably represents a central mechanism for regulation of gene transcription, and recent studies showed that numerous gene expressions are regulated by nucleosomal histone acetylation, which is modulated through histone acetyltransferases (HATs) and histone deacetylases (HDACs). So we have a hypothesis that the AMPK regulates GLUT4 gene through recruiting HDACs. Skeletal muscle cells cultured with normal (5 mmol/L) and high (20 mmol/L) glucose concentration were incubated with AICAR, and then total and nuclear AMPKalpha2, HDAC5 protein and GLUT4 mRNA were measured. The results show that the AICAR activated AMPKalpha2, reduced nuclear HDAC5,and increased GLUT4 mRNA in skeletal muscle cells; in contrast, the effect evoked by AICAR was blunted in cultured skeletal muscle cells with high glucose. Therefore, the changes of GLUT4 gene expression under different glucose concentration are closely related to the changes of AMPKalpha2 and HDAC5 protein in skeletal muscle cells. This result demonstrates that HDAC5 plays an important role in regulating GLUT4 gene transcription by AMPK signaling pathway skeletal muscle cells.
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PMID:[Mechanism of AMPK regulating GLUT4 gene expression in skeletal muscle cells]. 1843 82

Osteoblast apoptosis reduces bone mineral density. Apoptosis can be induced in a variety of cells by palmitate, which is one of the most common saturated fatty acids in dietary fat. The AMPK activator, AICAR, has been shown to inhibit palmitate-induced apoptosis. However, the role of palmitate in osteoblast apoptosis is currently unknown. This study examined whether palmitate could induce apoptosis in osteoblasts, and if so, whether AICAR could alleviate palmitate-induced apoptosis. Palmitate reduced cell survival and induced apoptosis in a dose- and time-dependent manner in human fetal osteoblasts (hFOB) 1.19. While the long-chain acyl-CoA synthetase inhibitor, triacsin C, inhibited palmitate-induced apoptosis, anti-oxidants and ceramide synthesis inhibitors did not attenuate the apoptosis. AICAR prevented palmitate-induced apoptosis and the inhibition of AICAR-mediated increase in fatty acid oxidation by etomoxir did not affect the prevention of apoptosis by AICAR. Constitutively-active AMPK also inhibited palmitate-induced apoptosis. Treatment with an AMPK inhibitor (compound C) and a dominant-negative AMPK adenovirus suppressed the inhibitory effect of AICAR on apoptosis. Palmitate impaired the activation of ERK by fetal bovine serum, which was blocked by AICAR. Moreover, AICAR increased ERK activation, and ERK inhibitors, PD98059 and U0126, as well as a dominant-negative MEK1, abolished the inhibitory effect of AICAR on palmitate-induced apoptosis. AICAR also inhibited palmitate-induced apoptosis in osteoblastic differentiated cells from human bone marrow, which was accompanied by recovered ERK activity. These results suggest that palmitate induces apoptosis in osteoblasts through the impaired activation of ERK, and the activation of AMPK inhibits palmitate-induced apoptosis by activating ERK.
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PMID:AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. 1850 15

Decreasing muscle phosphagen content through dietary administration of the creatine analog beta-guanidinopropionic acid (beta-GPA) improves skeletal muscle oxidative capacity and resistance to fatigue during aerobic exercise in rodents, similar to that observed with endurance training. Surprisingly, the effect of beta-GPA on muscle substrate metabolism has been relatively unexamined, with only a few reports of increased muscle GLUT4 content and insulin-stimulated glucose uptake/clearance in rodent muscle. The effect of chronically decreasing muscle phophagen content on muscle fatty acid (FA) metabolism (transport, oxidation, esterification) is virtually unknown. The purpose of the present study was to examine changes in muscle substrate metabolism in response to 8 wk feeding of beta-GPA. Consistent with other reports, beta-GPA feeding decreased muscle ATP and total creatine content by approximately 50 and 90%, respectively. This decline in energy charge was associated with simultaneous increases in both glucose (GLUT4; +33 to 45%, P < 0.01) and FA (FAT/CD36; +28 to 33%, P < 0.05) transporters in the sarcolemma of red and white muscle. Accordingly, we also observed significant increases in insulin-stimulated glucose transport (+47%, P < 0.05) and AICAR-stimulated palmitate oxidation (+77%, P < 0.01) in the soleus muscle of beta-GPA-fed animals. Phosphorylation of AMPK (+20%, P < 0.05), but not total protein, was significantly increased in both fiber types in response to muscle phosphagen reduction. Thus the content of sarcolemmal transporters for both of the major energy substrates for muscle increased in response to a reduced energy charge. Increased phosphorylation of AMPK may be one of the triggers for this response.
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PMID:Decreasing intramuscular phosphagen content simultaneously increases plasma membrane FAT/CD36 and GLUT4 transporter abundance. 1865 Mar 14

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.
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PMID:AMPK and PPARdelta agonists are exercise mimetics. 1867 9

The mechanisms by which PGC-1alpha gene expression is controlled in skeletal muscle remains largely undefined. Thus, we sought to investigate the transcriptional regulation of PGC-1alpha using AICAR, an activator of AMPK, that is known to increase PGC-1alpha expression. A 2.2 kb fragment of the human PGC-1alpha promoter was cloned and sequence analysis revealed that this TATA-less sequence houses putative consensus sites including a GC-box, a CRE, several IRSs, a SRE, binding sites for GATA, MEF2, p 53, NF-kappaB, and EBox binding proteins. AMPK activation for 24 hours increased PGC-1alpha promoter activity with concomitant increases in mRNA expression. The effect of AICAR on transcriptional activation was mediated by an overlapping GATA/EBox binding site at -495 within the PGC-1alpha promoter based on gel shift analyses that revealed increases in GATA/EBox DNA binding. Mutation of the EBox within the GATA/EBox binding site in the promoter reduced basal promoter activity and completely abolished the AICAR effect. Supershift analyses identified USF-1 as a DNA binding transcription factor potentially involved in regulating PGC-1alpha promoter activity, which was confirmed in vivo by ChIP. Overexpression of either GATA-4 or USF-1 alone increased the p851 PGC-1alpha promoter activity by 1.7- and 2.0-fold respectively, while co-expression of GATA-4 and USF-1 led to an additive increase in PGC-1alpha promoter activity. The USF-1-mediated increase in PGC-1alpha promoter activation led to similar increases at the mRNA level. Our data identify a novel AMPK-mediated regulatory pathway that regulates PGC-1alpha gene expression. This could represent a potential therapeutic target to control PGC-1alpha expression in skeletal muscle.
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PMID:AMP-activated protein kinase-regulated activation of the PGC-1alpha promoter in skeletal muscle cells. 1897 83

SNARK, a member of the AMPK-related kinases, has been involved in the cellular stress responses but its precise mechanisms remain unclear. Subcellular localization of SNARK protein was identified. Unlike cytoplasmic localizing AMPKalpha, SNARK was predominantly localized in the nucleus. SNARK was constitutively distributed in the nucleus even when SNARK was activated by metabolic stimuli such as AICAR and glucose-deprivation. Conserved nuclear localization signal (NLS) was identified at the N-terminal portion ((68)KKAR(71)). Deletion and point mutation of this part resulted in the cytoplasmic translocation of mutant proteins. Furthermore, GFP fused with the SNARK fragment containing (68)KKAR(71) translocated to the nucleus. A microarray analysis revealed that the nuclear localizing SNARK altered transcriptome profiles and a considerable part of these alterations were canceled by the mutation of NLS, suggesting the ability of SNARK to modulate gene expression dependent on its nuclear localization.
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PMID:Nuclear localization of SNARK; its impact on gene expression. 1899 19

Fatty Acid Synthase (FASN), a 250-kDa cytosolic multi-enzyme catalyzing eukaryotic de novo FA biogenesis, unexpectedly localizes in cancer cell culture supernatants and in the blood of cancer patients. High levels of "extracellular FASN" have recently been found in supernatants from Hepatitis C Virus-infected liver cells. The ultimate mechanism regulating FASN release, however, remained completely undefined. When the AMPK-activating drug AICAR was used to simulate an elevated AMP/ATP ratio in breast cancer cells, ELISA-based analyses revealed that extracellular FASN dramatically augmented in a dose- and time-dependent manner. Immunoblotting procedures using a battery of anti-FASN antibodies further confirmed that, in response to AMPK activation, FASN protein is depleted from the cytosol to accumulate as different FASN isoforms in the extracellular milieu. siRNA-induced blockade of AMPK expression largely attenuated AICAR-promoted FASN release. FASN release might represent a previously unrecognized mechanism through which AMPK monitor and restores cellular energy state in response to increasing AMP/ATP ratios.
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PMID:AMPK-sensed cellular energy state regulates the release of extracellular Fatty Acid Synthase. 1903 40

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

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the K(ATP) channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 microM). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.
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PMID:Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose. 1922 52


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