Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colorectal cancer cells are unique in that they escape Fas-mediated cell death in the presence of Fas ligand, and we recently reported that AMP-activated protein kinase-related kinase 5 (ARK5) suppresses cell death signaling mediated by cell death receptor in Akt-dependent manner. In the current study, therefore, we examined whether ARK5 is involved in the escape from Fas-mediated cell death of colorectal cancer cells. Among 10 cell lines, ARK5 mRNA expression was observed in LoVo, SW480, and SW1116 cell lines. Interestingly, SW480 and SW1116 cell lines, but not LoVo cell line, showed expressions of both Fas ligand (FasL) and Fas mRNAs. SW620 cell line also showed FasL mRNA; however, Fas and ARK5 mRNAs were not detected. Furthermore, well-coincided expression among ARK5, FasL, and Fas mRNAs was observed in tumor tissues from patients with colorectal cancer, suggesting the suppression of FasL/Fas system-induced cell death by ARK5 in colorectal cancer cell lines. Intensive cell death, which was dependent on the FasL/Fas system was encountered when ARK5 antisense RNA (ARK5/AS) was introduced into SW480 cells. FLIP was expressed in only ARK5 mRNA-expressing cell lines, and ARK5/AS induced FLIP cleavage in a caspase-6-dependent manner. Amino-acid sequence analysis of caspase-6 revealed two putative sites of phosphorylation by ARK5 at Ser80 and Ser257. Although active caspase-6 overexpression induced cell death in SW480 and DLD-1 cell lines, SW480 cells, but not DLD-1 cells, exhibited strong resistance to procaspase-6 overexpression. Moreover, mutant caspase-6, in which the Ser257 was substituted by Ala (caspase-6/SA), induced cell death and FLIP degradation, even in SW480 cells. Active ARK5 was found to phosphorylate wild-type caspase-6 in vitro, but not caspase-6/SA, and the prevented activation of caspase-6 was promoted due to its phosphorylation by active ARK5 in vitro. On the basis of the results of this study, we propose that ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system.
Oncogene 2004 Sep 16
PMID:Regulation of caspase-6 and FLIP by the AMPK family member ARK5. 1527 17

AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor that regulates glucose and lipid metabolism by phosphorylating key regulatory enzymes. Despite the major role of adipose tissue in regulating energy partitioning in the organism, the role of AMPK in this tissue has not been addressed. In the present study, we subjected AMPKalpha2 knockout (KO) mice to a high-fat diet to examine the effect of AMPK on adipose tissue formation. Compared with the wild type, AMPKalpha2 KO mice exhibited increased body weight and fat mass. The increase in adipose tissue mass was due to the enlargement of the preexisting adipocytes with increased lipid accumulation. However, we did not observe any changes in adipocyte marker expression, such as peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and adipocyte fatty acid-binding protein (aFABP/aP2), or total cell number. Unlike impaired glucose homeostasis observed on normal diet feeding, when fed a high-fat diet AMPKalpha2 KO mice did not show differences in glucose tolerance and insulin sensitivity compared with wild-type mice. Our results suggest that the increase in lipid storage in adipose tissue in AMPKalpha2 KO mice may have protected these mice from further impairment of glucose homeostasis that normally accompanies high-fat feeding. Our study also demonstrates that lack of AMPKalpha2 subunit may be a factor contributing to the development of obesity.
Diabetes 2004 Sep
PMID:Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit. 1533 33

Three kinases, Pak1, Tos3, and Elm1, activate Snf1 protein kinase in Saccharomyces cerevisiae. This cascade is conserved in mammals, where LKB1 activates AMP-activated protein kinase. We address the specificity of the activating kinases for the three forms of Snf1 protein kinase containing the beta-subunit isoforms Gal83, Sip1, and Sip2. Pak1 is the most important kinase for activating Snf1-Gal83 in response to glucose limitation, but Elm1 also has a significant role; moreover, both Pak1 and Elm1 affect Snf1-Sip2. These findings exclude the possibility of a one-to-one correspondence between the activating kinases and the Snf1 complexes. We further identify a second, unexpected role for Pak1 in regulating Snf1-Gal83: the catalytic activity of Pak1 is required for the nuclear enrichment of Snf1-Gal83 in response to carbon stress. The nuclear enrichment of Snf1 fused to green fluorescent protein (GFP) depends on both Gal83 and Pak1 and is abolished by a mutation of the activation loop threonine; in contrast, the nuclear enrichment of Gal83-GFP occurs in a snf1Delta mutant and depends on Pak1 only when Snf1 is present. Snf1-Gal83 is the only form of the kinase that localizes to the nucleus. These findings, that Pak1 both activates Snf1-Gal83 and controls its nuclear localization, implicate Pak1 in regulating nuclear Snf1 protein kinase activity.
Mol Cell Biol 2004 Sep
PMID:Pak1 protein kinase regulates activation and nuclear localization of Snf1-Gal83 protein kinase. 1534 85

The physiologic function of the progressive hyperleptinemia of diet-induced obesity is unknown. However, that lipotoxicity in nonadipose tissues of congenitally unleptinized obese rodents is far greater than in hyperleptinemic diet-induced obesity rodents has suggested an antilipotoxic role. To test this hypothesis, mice with severe lipotoxic cardiomyopathy, induced transgenically by cardiomyocyte-specific overexpression of the acyl CoA synthase (ACS) gene, were made hyperleptinemic by treatment with recombinant adenovirus containing the leptin cDNA. Normoleptinemic control ACS-transgenic mice developed severe dilated cardiomyopathy with thickened left ventricular walls and profound impairment of systolic function on echocardiogram; histologically, there was severe myofiber disorganization and interstitial fibrosis, with intracytoplasmic lipid vacuoles identifiable by electron microscope. By contrast, the hearts of hyperleptinemic ACS-transgenic mice appeared normal, with normal echocardiograms and cardiac triglyceride (TG) contents. Their lower myocardial TG content was ascribed primarily to profound lowering of plasma TG and free fatty acids; free fatty acids were 17% of normal at 8 weeks. Additionally, enhanced myocardial AMP-activated protein kinase phosphorylation may have increased fatty acid oxidation, thereby contributing to the lowering of lipid stores. We conclude that obesity-level hyperleptinemia protects the heart from lipotoxicity.
Proc Natl Acad Sci U S A 2004 Sep 14
PMID:Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice. 1534 5

Obesity in humans is associated with lipid accumulation in skeletal muscle, insulin and leptin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) is an important regulator of fatty acid (FA) metabolism in skeletal muscle. To address the hypothesis that lipid accumulation in skeletal muscle of obese subjects may be due to down-regulation of AMPK, we measured mRNA and protein levels of AMPK isoforms, AMPKalpha1 and -alpha2 activity, AMPK kinase activity, acetyl-coenzyme A carboxylase (ACCbeta) expression and phosphorylation, and FA metabolism in biopsies of rectus abdominus muscle from lean and obese women. We also examined the effect of 5-aminoimidazole-4-carboxamide riboside (AICAR) on AMPK activity and the effects of AICAR and leptin on FA metabolism. Skeletal muscle of obese subjects had increased total FA uptake and triglyceride esterification, and leptin failed to stimulate FA oxidation. However, AMPK mRNA and protein expression, AMPKalpha1 and -alpha2 activities, AMPK kinase activity, ACCbeta phosphorylation, and FA oxidation were similar in lean and obese subjects. Moreover, AICAR increased AMPKalpha2 activity, ACCbeta phosphorylation, and palmitate oxidation to a similar degree in muscle from lean and obese subjects. We conclude that the abnormal lipid metabolism and leptin resistance of skeletal muscle of obese subjects is not due to down-regulation of AMPK. In addition, the similar stimulation by AICAR of AMPK in skeletal muscle of lean and obese subjects suggests that direct pharmacological activation of AMPK may be a therapeutic approach for stimulating FA oxidation in the treatment of human obesity.
J Clin Endocrinol Metab 2004 Sep
PMID:AMP-activated protein kinase is not down-regulated in human skeletal muscle of obese females. 1535 65

Myocardial fatty acid oxidation is regulated by carnitine palmitoyltransferase I (CPT I), which is inhibited by malonyl-CoA. Increased cardiac power causes a fall in malonyl-CoA content and accelerated fatty acid oxidation; however, the mechanism for the decrease in malonyl-CoA is unclear. Malonyl-CoA is formed by acetyl-CoA carboxylase (ACC) and degraded by malonyl-CoA decarboxylase (MCD); thus a fall in malonyl-CoA could be due to activation of MCD, inhibition of ACC, or both. This study assessed the effects of increased cardiac power on malonyl-CoA content and ACC and MCD activities. Anesthetized pigs were studied under control conditions and during increased cardiac power in response to dobutamine infusion and aortic constriction alone, under hyperglycemic conditions, or with the CPT I inhibitor oxfenicine. An increase in cardiac power was accompanied by increased myocardial O(2) consumption, decreased malonyl-CoA concentration, and increased fatty acid oxidation. There were no differences among groups in activity of ACC or AMP-activated protein kinase (AMPK), which physiologically inhibits ACC. There also were no differences in V(max) or K(m) of MCD. Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity. In conclusion, the fall in malonyl-CoA and increase in fatty acid oxidation that occur with increased cardiac work were not due to inhibition of ACC or activation of MCD, suggesting alternative regulatory mechanisms for the work-induced decrease in malonyl-CoA concentration.
Am J Physiol Heart Circ Physiol 2005 Sep
PMID:Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power. 1582 Oct 35

Sensitivity of glucose transport to stimulation by insulin has been shown to occur concomitant with activation of the AMP-activated protein kinase (AMPK) in skeletal muscle, suggesting a role of AMPK in regulation of insulin action. The purpose of the present study was to evaluate a possible role of AMPK in potentiation of insulin action in muscle cells. The experimental model involved insulin-responsive C2C12 myotubes that exhibit a twofold increase in glucose transport in the presence of insulin. Treatment of myotubes with the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), followed by a 2-h recovery, augmented the ability of insulin to stimulate glucose transport. Similarly, incubation in hyperosmotic medium, another AMPK-activating treatment, acted synergistically with insulin to stimulate glucose transport. Furthermore, the increase in insulin action caused by hyperosmotic stress was prevented by inclusion of compound C, an AMPK inhibitor, in hyperosmotic medium. In addition, iodotubercidin, a general kinase inhibitor that is effective against AMPK, also prevented the combined effects of insulin and hyperosmotic stress on glucose transport. The new information provided by these data is that previously reported AICAR effects on insulin action are generalizable to myotubes, hyperosmotic stress and insulin synergistically increase glucose transport, and AMPK appears to mediate potentiation of insulin action.
J Appl Physiol (1985) 2005 Sep
PMID:AICAR and hyperosmotic stress increase insulin-stimulated glucose transport. 1586 Jun 81

AMP-activated protein kinase (AMPK) regulates both glycogen and lipid metabolism functioning as an intracellular energy sensor. In this study, we identified a 160-kDa protein in mouse skeletal muscle lysate by using a glutathione-S-transferase (GST)-AMPK fusion protein pull-down assay. Mass spectrometry and a Mascot search revealed this protein to be a glycogen debranching enzyme (GDE). The association between AMPK and GDE was observed not only in the overexpression system but also endogenously. Next, we showed the beta1-subunit of AMPK to be responsible for the association with GDE. Furthermore, experiments using deletion mutants of the beta1-subunit of AMPK revealed amino acids 68-123 of the beta1-subunit to be sufficient for GDE binding. W100G and K128Q, both beta1-subunit mutants, are reportedly incapable of binding to glycogen, but both bound GDE, indicating that the association between AMPK and GDE does not involve glycogen. Rather, the AMPK-GDE association is likely to be direct. Overexpression of amino acids 68-123 of the beta1-subunit inhibited the association between endogenous AMPK and GDE. Although GDE activity was unaffected, basal phosphorylation and kinase activity of AMPK, as well as phosphorylation of acetyl-CoA carboxylase, were significantly increased. Thus it is likely that the AMPK-GDE association is a novel mechanism regulating AMPK activity and the resultant fatty acid oxidation and glucose uptake.
Am J Physiol Endocrinol Metab 2005 Sep
PMID:Glycogen debranching enzyme association with beta-subunit regulates AMP-activated protein kinase activity. 1588 29

Mechanisms regulating ischemia and reperfusion (I/R)-induced changes in mRNA translation in the heart are poorly defined, as are the factors that initiate these changes. Because cellular energy status affects mRNA translation under physiological conditions, it is plausible that I/R-induced changes in translation may in part be a result of altered cellular energy status. Therefore, the purpose of the studies described herein was to compare the effects of I/R with those of altered energy substrate availability on biomarkers of mRNA translation in the heart. Isolated adult rat hearts were perfused with glucose or a combination of glucose plus palmitate, and effects of I/R on various biomarkers of translation were subsequently analyzed. When compared with hearts perfused with glucose plus palmitate, hearts perfused with glucose alone exhibited increased phosphorylation of eukaryotic elongation factor (eEF)2, the alpha-subunit of eukaryotic initiation factor (eIF)2, and AMP-activated protein kinase (AMPK), and these hearts also exhibited enhanced association of eIF4E with eIF4E binding protein (4E-BP)1. Regardless of the energy substrate composition of the buffer, phosphorylation of eEF2 and AMPK was greater than control values after ischemia. Phosphorylation of eIF2alpha and eIF4E and the association of eIF4E with 4E-BP1 were also greater than control values after ischemia but only in hearts perfused with glucose plus palmitate. Reperfusion reversed the ischemia-induced increase in eEF2 phosphorylation in hearts perfused with glucose and reversed ischemia-induced changes in eIF4E, eEF2, and AMPK phosphorylation in hearts perfused with glucose plus palmitate. Because many ischemia-induced changes in mRNA translation are mimicked by the removal of a metabolic substrate under normal perfusion conditions, the results suggest that cellular energy status represents an important modulator of I/R-induced changes in mRNA translation.
Am J Physiol Heart Circ Physiol 2005 Sep
PMID:Cellular energy status modulates translational control mechanisms in ischemic-reperfused rat hearts. 1589 72

Skeletal muscle is composed of fast- and slow-twitch fibres with distinctive physiological and metabolic properties. The calmodulin-activated serine/threonine protein phosphatase calcineurin activates fast- to slow-twitch skeletal muscle remodelling through the induction of the slow-twitch skeletal muscle fibre gene expression programme, thereby enhancing insulin-stimulated glucose uptake and offering protection against dietary-induced insulin resistance. Given the profound influence of skeletal muscle fibre type on insulin-mediated responses, we determined whether the fast- to slow-twitch fibre-type transformation leads to alterations in insulin-independent glucose uptake in transgenic mice expressing a constitutively active form of calcineurin (MCK-CnA* mice). We determined whether skeletal muscle remodelling by activated calcineurin alters glucose transport in response to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-beta-D-ribofuranoside (AICAR) or muscle contraction, two divergent insulin-independent activators of glucose transport. While insulin-stimulated glucose transport was increased 52%, the AICAR effect on glucose transport was 27% lower in MCK-CnA* mice versus wild-type mice (P < 0.05). In contrast, glucose transport was similar between genotypes after in vitro muscle contraction. Fibre-type transformation was associated with increased AMPKgamma1, decreased AMPKgamma3 and unchanged AMPKgamma2 protein expression between MCK-CnA* and wild-type mice (P < 0.05). The loss of AICAR-mediated glucose uptake is coupled to changes in the AMPK isoform expression, suggesting fibre-type dependence of the AICAR responses on glucose uptake. In conclusion, improvements in skeletal muscle glucose transport in response to calcineurin-induced muscle remodelling are limited to insulin action.
J Physiol 2005 Sep 01
PMID:Effects of calcineurin activation on insulin-, AICAR- and contraction-induced glucose transport in skeletal muscle. 1597 79


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