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:2.7.11.31 (AMP-activated protein kinase)
13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1 alpha expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.
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PMID:AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. 3044 3

The induction of proangiogenic cytokines such as vascular endothelial growth factor (VEGF) is a critical feature of tumor angiogenesis. In the present study, we examined the mechanisms of VEGF gene expression induced by glucose deprivation in cancer cells, a role of AMP-activated protein kinase (AMPK) in the process, and the signal transduction pathway. AMPK functions as an energy sensor to provide metabolic adaptation under ATP-depleting conditions such as hypoxia and nutritional deprivation. Here, we show that glucose deprivation leads to a significant increase in the mRNA level of VEGF, GLUT1, and PFKFB3 genes in several cancer cells via a hypoxia-inducible factor-1-independent mechanism, and we demonstrate an essential role of AMPK in these gene expressions. Our data suggest that VEGF mRNA induction by glucose deprivation is due to an increase in mRNA stability, and the AMPK activity is necessary and sufficient to confer the stability to VEGF mRNA. We further show that reactive oxygen species is involved in glucose deprivation-induced AMPK activity in DU145 human prostate carcinomas, and c-Jun amino-terminal kinase acts as an upstream component in AMPK activation cascades under these conditions. LKB1, which was recently identified as a direct upstream kinase of AMPK, was not detected in DU145 cells. In conclusion, our results demonstrate a novel and major role of AMPK in the post-transcriptional regulation of VEGF, further implying its potential role in tumor angiogenesis.
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PMID:Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. 3044 4

Insulin, insulin like growth factor (IGF)-1, and AMP-activated protein kinase (AMPK) signaling regulate independently angiogenesis through vascular endothelial growth factor (VEGF) expression. In the present study, we investigated a potential cross-talk between these signaling pathways on hypoxia-inducible factor (HIF)-1alpha and VEGF expression. Retinal epithelial ARPE-19 cells were treated with AICAR, an AMPK activator, alone or in combination with insulin and IGF-1. AICAR stimulated VEGF mRNA expression, but did not modify the insulin- and IGF-1-induced VEGF expression. We have investigated the effect of AICAR on insulin and IGF-1 signaling pathways. We observed that AICAR increased insulin- and IGF-1-induced phosphorylation of PKB, whereas phosphorylation of S6K-1 was decreased. Moreover, AICAR and metformin inhibited the ability of insulin and IGF-1 to induce HIF-1alpha expression. These results show that AICAR and insulin/IGF-1 regulate VEGF expression through different mechanisms.
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PMID:AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1. 1651 66

EGCG [(-)epigallocatechin-3-gallate], a green tea-derived polyphenol, has been shown to suppress cancer cell proliferation, and interfere with the several signaling pathways and induce apoptosis. Practically, there is emerging evidence that EGCG has a potential to increase the efficacy of chemotherapy in patients. We hypothesized that EGCG may exert cell cytotoxicity through modulating AMPK (AMP-activated protein kinase) followed by the decrease in COX-2 expression. EGCG treatment to colon cancer cells resulted in a strong activation of AMPK and an inhibition of COX-2 expression. The decreased COX-2 expression as well as prostaglandin E(2) secretion by EGCG was completely abolished by inhibiting AMPK by an AMPK inhibitor, Compound C. Also, the activation of AMPK was accompanied with the reduction of VEGF (vascular endothelial growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells. These findings support the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells. Furthermore, we have found that reactive oxygen species (ROS) is an upstream signal of AMPK, and the combined treatment of EGCG and chemotherapeutic agents, 5-FU or Etoposide, exert a novel therapeutic effect on chemo-resistant colon cancer cells. AMPK, a molecule of newly defined cancer target, was shown to control COX-2 in EGCG-treated colon cancer cells.
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PMID:Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway. 1679 20

Adiponectin, the most abundantly synthesized protein in adipose tissue, has plieotropic effects on liver, muscle, endothelium, placenta, and other tissues. We examined direct effects of recombinant porcine adiponectin on porcine ovarian granulosa cells in vitro. We demonstrate that adiponectin, at physiologically relevant levels (10-25 microg/ml), provokes expression of genes associated with periovulatory remodeling of the ovarian follicle over a time frame of 6-24 h. These include cyclooxygenase-2, prostaglandin E synthase, and vascular endothelial growth factor. Adiponectin modulates steroid synthetic protein gene expression, increasing steroidogenic acute regulatory protein transcript abundance and reducing cytochrome P450aromatase. Adiponectin has antidiabetic properties and sensitizes tissues to insulin. We show that it interacts with both LH and insulin in inducing expression of cyclooxygenase-2 transcripts in granulosa cells. We determined that the MAPK pathway, via phosphorylation of ERK1/2, is involved in mediation of the adiponectin signal in ovarian granulosa cells, rather than protein kinase A or the classic adiponectin transducer, AMP-activated protein kinase. Adiponectin synthesis is reduced in obesity, and our findings suggest that this reduction plays a role in obesity-related ovarian dysfunction.
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PMID:Adiponectin induces periovulatory changes in ovarian follicular cells. 1691 53

Cerebrovascular dysfunction appears to be involved in Alzheimer's disease (AD). In double mutant amyloid precursor protein/presenilin 2 (APP/PS2) mice, a transgenic model of AD, vessel homeostasis is disturbed. These mice have elevated levels of vascular endothelial growth factor (VEGF) and increased brain endothelial cell division but abnormally low brain vessel density. Examination of the potential involvement of insulin-like growth factor I (IGF-I) in these alterations revealed that treatment with IGF-I, a potent vessel growth promoter in the brain that ameliorates cognitive dysfunction in APP/PS2 mice, counteracted vascular dysfunction as follows: VEGF levels and endothelial cell proliferation were reduced, whereas vascular density was normalized. Notably, abnormally elevated brain IGF-I receptor levels in APP/PS2 mice were also normalized by IGF-I treatment. Analysis of possible processes involved in these alterations indicated that AMP-activated protein kinase (AMPK), a cell energy sensor that intervenes in angiogenic signaling and interacts with IGF-I, was also abnormally activated in APP/PS2 brains. Examination of the consequences of AMPK activation on cultured brain endothelial cells revealed increased VEGF levels together with enhanced endothelial cell proliferation and metabolism. Although these effects were also independently elicited by IGF-I, when both IGF-I and AMPK pathways were simultaneously activated on brain endothelial cells, VEGF production and endothelial cell proliferation ceased while cells remained metabolically activated (glucose use, peroxide production, and mitochondrial activity were elevated) and became more resistant to oxidative stress. Therefore, high IGF-I receptor and phosphoAMPK levels in APP/PS2 brains may reflect imbalanced IGF-I and AMPK angiogenic cross talk that could underlie vascular dysfunction in this model of AD.
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PMID:Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. 1725 22

Fenofibrate, a widely used hypolipidemic drug, has anti-inflammatory and anti-atherosclerotic effects in the vessel wall. In the present study, we report an anti-apoptotic property of fenofibrate in human retinal endothelial cells (HRECs) and describe an underlying molecular mechanism. Treatment with fenofibrate protected HRECs from apoptosis in response to serum deprivation in a dose-dependent manner. This inhibition of apoptosis by fenofibrate was not altered by peroxisome proliferator-activated receptor alpha (PPARalpha) antagonist MK 886, and selective agonist for PPARalpha, WY-14643 had no beneficial effects on serum deprivation-induced cell death. Fenofibrate potently induced a sustained activation of AMP-activated protein kinase (AMPK) and vascular endothelial growth factor (VEGF) mRNA expression. Furthermore, compound C, a specific AMPK inhibitor, almost completely blocked the fenofibrate-induced survival effect as well as VEGF mRNA expression. Taken together, these results suggest that fenofibrate prevents apoptotic cell death induced by serum deprivation through PPARalpha-independent, but AMPK-dependent pathway. Thus fenofibrate may have a novel therapeutic property that can control unwanted cell death found in diabetic retinopathy.
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PMID:Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway. 1734 53

Cytochrome P-450 (CYP) epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acid (EET) regioisomers, which activate several signaling pathways to promote endothelial cell proliferation, migration, and angiogenesis. Since vascular endothelial growth factor (VEGF) plays a key role in angiogenesis, we assessed a possible role of EETs in the VEGF-activated signal transduction cascade. Stimulation with VEGF increased CYP2C promoter activity in endothelial cells and enhanced CYP2C8 mRNA and protein expression resulting in increased intracellular EET levels. VEGF-induced endothelial cell tube formation was inhibited by the EET antagonist 14,15-epoxyeicosa-5(Z)-enoicacid (14,15-EEZE), which did not affect the VEGF-induced phosphorylation of its receptor or basic fibroblast growth factor (bFGF)-stimulated tube formation. Moreover, VEGF-stimulated endothelial cell sprouting in a modified spheroid assay was reduced by CYP2C antisense oligonucleotides. Mechanistically, VEGF stimulated the phosphorylation of the AMP-activated protein kinase (AMPK), which has also been linked to CYP induction, and the overexpression of a constitutively active AMPK mutant increased CYP2C expression. On the other hand, a dominant-negative AMPK mutant prevented the VEGF-induced increase in CYP2C RNA and protein expression in human endothelial cells. In vivo (Matrigel plug assay) in mice, endothelial cells were recruited into VEGF-impregnated plugs; an effect that was sensitive to 14,15-EEZE and the inclusion of small interfering RNA directed against the AMPK. The EET antagonist did not affect responses observed in plugs containing bFGF. Taken together, our data indicate that CYP2C-derived EETs participate as second messengers in the angiogenic response initiated by VEGF and that preventing the increase in CYP expression curtails the angiogenic response to VEGF.
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PMID:Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis. 1878 75

5'-AMP-activated protein kinase (AMPK) is a metabolic fuel sensor that monitors cellular energy charge, while the vasculature is important for maintaining cellular energy homeostasis. Mice with muscle-specific inactive AMPK (AMPK DN) were used to investigate if AMPK regulates skeletal muscle capillarization and the angiogenic responses to exercise. Two hours of the AMP analogue AICAR (1.0 g kg(-1)) or systemic hypoxia (6% O(2)) increased vascular endothelial growth factor (VEGF) mRNA in wild-type (WT), but not in AMPK DN mice. In contrast, the increase in VEGF mRNA with acute exercise (1 h at 20 m min(-1), 10% gradient) was greater in AMPK DN compared to WT mice. Nuclear run-on assay demonstrated that exercise increased VEGF transcription, while hypoxia decreased VEGF transcription. There was no difference in VEGF transcription between WT and AMPK DN. There was a strong correlation between VEGF transcription and VEGF mRNA at rest and with exercise. Resting capillarization was lower in AMPK DN compared to WT. Wheel running (28 days) increased capillarization and this response was AMPK independent. Significant correlations between VEGF protein and muscle capillarization are consistent with VEGF being an important determinant of skeletal muscle capillarization. These data are to our knowledge the first to demonstrate in skeletal muscle in vivo that: (1) AMPK is necessary for hypoxia-induced VEGF mRNA stabilization, (2) acute exercise increases VEGF transcription, (3) inhibition of AMPK augments the VEGF mRNA response to acute exercise, and (4) AMPK regulates basal VEGF expression and capillarization, but is not necessary for exercise-induced angiogenesis.
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PMID:AMPK regulates basal skeletal muscle capillarization and VEGF expression, but is not necessary for the angiogenic response to exercise. 1895 83

Angiogenesis is necessary for the growth of adipose tissue. Dietary polyphenols may suppress growth of adipose tissue through their antiangiogenic activity and by modulating adipocyte metabolism. We investigated the effect of curcumin, the major polyphenol in turmeric spice, on angiogenesis, adipogenesis, differentiation, apoptosis, and gene expression involved in lipid and energy metabolism in 3T3-L1 adipocyte in cell culture systems and on body weight gain and adiposity in mice fed a high-fat diet (22%) supplemented with 500 mg curcumin/kg diet for 12 wk. Curcumin (5-20 micromol/L) suppressed 3T3-L1 differentiation, caused apoptosis, and inhibited adipokine-induced angiogenesis of human umbilical vein endothelial cells. Supplementing the high-fat diet of mice with curcumin did not affect food intake but reduced body weight gain, adiposity, and microvessel density in adipose tissue, which coincided with reduced expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. Curcumin increased 5'AMP-activated protein kinase phosphorylation, reduced glycerol-3-phosphate acyl transferase-1, and increased carnitine palmitoyltransferase-1 expression, which led to increased oxidation and decreased fatty acid esterification. The in vivo effect of curcumin on the expression of these enzymes was also confirmed by real-time RT-PCR in subcutaneous adipose tissue. In addition, curcumin significantly lowered serum cholesterol and expression of PPARgamma and CCAAT/enhancer binding protein alpha, 2 key transcription factors in adipogenesis and lipogenesis. The curcumin suppression of angiogenesis in adipose tissue together with its effect on lipid metabolism in adipocytes may contribute to lower body fat and body weight gain. Our findings suggest that dietary curcumin may have a potential benefit in preventing obesity.
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PMID:Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. 1929 23


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