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)

The LKB1 tumor suppressor protein controls the activity of the TSC1/TSC2 tumor suppressor complex. Mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), and mutations in either TSC1 or TSC2 cause tuberous sclerosis complex--two syndromes characterized by the development of hamartomas. LKB1 activation by energy deprivation activates AMPK, which in turn phosphorylates and activates TSC2. TSC2 activation results in the inactivation of mTOR, a critical regulator of protein translation. How mTOR dysregulation after inactivation of LKB1 or TSC1/2 contributes to hamartoma development is not known. However, hypoxia-inducible factor (HIF) and VEGF are regulated by mTOR and are likely to play a contributory role.
Cancer Cell 2004 Jul
PMID:Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. 1526 Nov 37

Germline mutations in LKB1, TSC2, or PTEN tumor suppressor genes result in hamartomatous syndromes with shared tumor biological features. The recent observations of LKB1-mediated activation of AMP-activated protein kinase (AMPK) and AMPK inhibition of mTOR through TSC2 prompted us to examine the biochemical and biological relationship between LKB1 and mTOR regulation. Here, we report that LKB1 is required for repression of mTOR under low ATP conditions in cultured cells in an AMPK- and TSC2-dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR. These findings position aberrant mTOR activation at the nexus of these germline neoplastic conditions and suggest the use of mTOR inhibitors in the treatment of Peutz-Jeghers syndrome.
Cancer Cell 2004 Jul
PMID:The LKB1 tumor suppressor negatively regulates mTOR signaling. 1526 Nov 45

Hypoxia-inducible factor 1 (HIF-1), a pivotal transcription factor composed of HIF-1alpha and HIF-1beta subunits, plays a major role in tumor progression by activating a number of genes critically involved in adaptation to hypoxia. HIF-1 is also induced by several carcinogenic metals. Vanadate, an environmental toxic metal, is considered as a potent inducer of tumors in animals and is reported to activate HIF-1 activity. However, the involved mechanisms are poorly understood. In the present study, we have examined the biochemical mechanisms of the vanadate-induced HIF-1 activation in cancer cells by primarily focusing on the role of AMP-activated protein kinase (AMPK), which plays an essential role as an energy sensor under ATP-deprived conditions. We demonstrate that AMPK was rapidly activated in response to vanadate in DU145 human prostate carcinoma, and that its activation preceded HIF-1alpha expression. Under this condition, inhibition of AMPK by a pharmacological and molecular approach dramatically abolished the vanadate-induced HIF-1alpha expression as well as HIF-1-mediated physiological responses. Phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling was also involved in vanadate-induced HIF-1alpha expression, but it was independent of AMPK signaling pathway. Moreover, we demonstrate a role of reactive oxygen species as an upstream signal for these two pathways. These results suggest that AMPK is a novel and critical component of HIF-1 regulation, further implying its involvement in vanadate-induced carcinogenesis.
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PMID:AMP-activated protein kinase activity is required for vanadate-induced hypoxia-inducible factor 1alpha expression in DU145 cells. 1529 73

We recently identified a novel human AMPK family member, ARK5, and discovered that is a major factor in Akt-dependent cancer cell survival and migration activity through activation of MT1-MMPs in vitro. The mRNA expression of other AMPK family members and ARK5 was measured using RT-PCR in human colorectal carcinoma cell lines DLD-1, WiDr, HCT-15, SW620, LoVo, SW480, and mRNA expression of AMPK-alpha1, SNARK, MELK and ARK5, but not AMPK-alpha2, was detected in every line. Quantitative-PCR (Q-PCR) to estimate the amount of ARK5 mRNA expression in the cell lines showed that there is a variety of ARK5 expressions among the cell lines and high expression was observed in a cell line derived from the metastatic lesion, LoVo. To determine the effect of ARK5 overexpression on metastasis in vivo, we established human pancreas cancer cell line PANC-1 stably transfected with ARK5 full-length expression vector (P/ARK) and DLD-1 stably transfected with the same vector (D/ARK). Migration assay showed a remarkable increase in the activity both in P/ARK and D/ARK, and an in vivo metastasis assay showed a marked increase of P/ARK in liver metastasis. Based on these observations, it is suggested that ARK5 expression is involved in cancer invasion and metastasis.
J Exp Clin Cancer Res 2004 Jun
PMID:Strong association of ARK5 with tumor invasion and metastasis. 1535 11

Serine/threonine protein kinase AMP-activated protein kinase (AMPK) is a key metabolic stress-responsive factor that promotes the adaptation of cells to their microenvironment. Elevated concentrations of intracellular AMP, caused by metabolic stress, are known to activate AMPK by phosphorylation of the catalytic subunit. Recently, the tumor suppressor serine/threonine protein kinase LKB1 was identified as an upstream kinases, AMPKKs. In the current study, we found that stimulation with growth factors also caused AMPK-alpha subunit phosphorylation. Interestingly, even an LKB1-nonexpressing cancer cell line, HeLa, exhibited growth factor-stimulated AMPK-alpha subunit phosphorylation, suggesting the presence of an LKB1-independent pathway for AMPK-alpha subunit phosphorylation. In the human pancreatic cancer cell line PANC-1, AMPK-alpha subunit phosphorylation promoted by IGF-1 was suppressed by antisense ataxia telangiectasia mutated (ATM) expression. We found that IGF-1 also induced AMPK-alpha subunit phosphorylation in the human normal fibroblast TIG103 cell line, but failed to do so in a human fibroblast AT2-KY cell line lacking ATM. Immunoprecipitates of ATM collected from IGF-1-stimulated cells also caused the phosphorylation of the AMPK-alpha subunit in vitro. IGF-1-stimulated ATM phosphorylation at both threonine and tyrosine residues, and our results demonstrated that the phosphorylation of tyrosine in the ATM molecule is important for AMPK-alpha subunit phosphorylation during IGF-1 signaling. These results suggest that IGF-1 induces AMPK-alpha subunit phosphorylation via an ATM-dependent and LKB1-independent pathway.
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PMID:IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner. 1548 51

Mutations in the LKB1 tumour suppressor threonine kinase cause the inherited Peutz-Jeghers cancer syndrome and are also observed in some sporadic cancers. Recent work indicates that LKB1 exerts effects on metabolism, polarity and proliferation by phosphorylating and activating protein kinases belonging to the AMPK subfamily. In vivo, LKB1 forms a complex with STRAD, an inactive pseudokinase, and MO25, an armadillo repeat scaffolding-like protein. Binding of LKB1 to STRAD-MO25 activates LKB1 and re-localises it from the nucleus to the cytoplasm. To learn more about the inherent properties of the LKB1-STRAD-MO25 complex, we first investigated the activity of 34 point mutants of LKB1 found in human cancers and their ability to interact with STRAD and MO25. Interestingly, 12 of these mutants failed to interact with STRAD-MO25. Performing mutagenesis analysis, we defined two binding sites located on opposite surfaces of MO25alpha, which are required for the assembly of MO25alpha into a complex with STRADalpha and LKB1. In addition, we demonstrate that LKB1 does not require phosphorylation of its own T-loop to be activated by STRADalpha-MO25alpha, and discuss the possibility that this unusual mechanism of regulation arises from LKB1 functioning as an upstream kinase. Finally, we establish that STRADalpha, despite being catalytically inactive, is still capable of binding ATP with high affinity, but that this is not required for activation of LKB1. Taken together, our findings reinforce the functional importance of the binding of LKB1 to STRAD, and provide a greater understanding of the mechanism by which LKB1 is regulated and activated through its interaction with STRAD and MO25.
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PMID:Analysis of the LKB1-STRAD-MO25 complex. 1556 63

The study of hereditary tumor syndromes has laid a solid foundation toward understanding the genetic basis of cancer. One of the latest examples comes from the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses, TSC is characterized by the appearance of benign tumors, most notably in the central nervous system, kidney, heart, lung, and skin. While classically described as "hamartomas," the pathology of the lesions has features suggestive of abnormal cellular proliferation, size, differentiation, and migration. Occasionally, tumors progress to become malignant (i.e., renal cell carcinoma). The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2. Cells undergo bi-allelic inactivation of either gene to give rise to tumors in a classic tumor suppressor "two-hit" paradigm. The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently. Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors responsible for Cowden's disease (PTEN), Peutz-Jeghers syndrome (LKB1), and familial polyposis (APC). Common sporadic cancers such as prostate, lung, colon, endometrium, and breast have ties to these genes, highlighting the potential role of the TSC proteins in human cancers. Rapamycin, a specific mTOR inhibitor, has potent antitumoral activities in preclinical models of TSC and is currently undergoing phase I/II clinical studies.
Cancer Invest 2004
PMID:The tuberous sclerosis complex genes in tumor development. 1556 17

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

The fuel-sensing enzyme 5'-AMP-activated protein kinase (AMPK) has a major role in the regulation of cellular lipid and protein metabolism in response to stimuli such as exercise, changes in fuel availability and the adipocyte-derived hormones leptin and adiponectin. Recent studies indicate that abnormalities in cellular lipid metabolism are involved in the pathogenesis of the metabolic syndrome, possibly because of dysregulation of AMPK and malonyl-CoA, a closely related molecule. As we discuss in this article, several findings also point to a link between AMPK and the growth and/or survival of some cancer cells. Thus, it has been demonstrated recently that the tumor suppressor LKB1 is a kinase that has a major role in phosphorylating and activating AMPK, and that another tumor suppressor, tuberous sclerosis complex 2, is phosphorylated and activated by AMPK. In addition, other studies indicate that mammalian homolog of target of rapamycin (mTOR), which has been implicated in the pathogenesis of insulin resistance and many types of cancer, is inhibited by AMPK.
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PMID:AMPK, the metabolic syndrome and cancer. 1568 Oct 23

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that plays a key role in the regulation of energy control. AMPK is activated in response to an increase in the ratio of AMP:ATP within the cell. Activation requires phosphorylation of threonine 172 within the catalytic subunit of AMPK by an upstream kinase. The identity of the upstream kinase in the cascade remained frustratingly elusive for many years, but was recently identified as LKB1, a kinase that is inactivated in a rare hereditary form of cancer called Peutz-Jeghers syndrome. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance within the cell. ATP-consuming, anabolic pathways, such as fatty acid synthesis and protein synthesis are switched-off, whereas ATP-generating, catabolic pathways, such as fatty acid oxidation and glycolysis, are switched-on. More recent studies have indicated, that AMPK plays an important role in the regulation of whole body energy metabolism. The adipocyte-derived hormones, leptin and adiponectin, activate AMPK in peripheral tissues, including skeletal muscle and liver, increasing energy expenditure. In the hypothalamus, AMPK is inhibited by leptin and insulin, hormones which suppress feeding, whilst ghrelin, a hormone that increases food intake, activates AMPK. Furthermore, direct pharmacological activation of AMPK in the hypothalamus by 5-aminoimidazole-4-carboxamide ribose increases food intake in rats, demonstrating that AMPK plays a direct role in the regulation of feeding. Taken together these findings indicate that AMPK has a pivotal role in regulating pathways that control both energy expenditure and energy intake.
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PMID:AMP-activated protein kinase: balancing the scales. 1573 42


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