A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis

Carling, David; Zammit, Victor A.; Hardie, D. Grahame

doi:10.1016/0014-5793(87)80292-2

Cited by 530 publications

(390 citation statements)

References 25 publications

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“…AMPK was first identified as an activity which, through the phosphorylation and inactivation of key biosynthetic enzymes [60], was responsible for rapidly shutting down fatty acid synthesis in the face of fuel depletion [58]. Subsequent cloning of the catalytic subunit of the enzyme [61] revealed that mammalian AMPK was a close homologue of the sucrose non-fermenting factor-1 complex in yeast and plants [62,63].…”

Section: Introductionmentioning

confidence: 99%

Visualising insulin secretion. The Minkowski Lecture 2004

Rutter

2004

Diabetologia

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Insulin secretion from pancreatic islet beta cells is a tightly regulated process, under the close control of blood glucose concentrations, neural inputs and circulating hormones. Defects in glucose-triggered insulin secretion, possibly exacerbated by a decrease in beta cell mass, are ultimately responsible for the development of type 2 diabetes. A full understanding of the mechanisms by which glucose and other nutrients trigger insulin secretion will probably be essential to allow for the development of new therapies of type 2 diabetes and for the derivation of "artificial" beta cells from embryonic stem cells as a treatment for type 1 diabetes. I focus here on recent developments in our understanding of beta cell glucose sensing, achieved in part through the development of recombinant targeted probes (luciferase, green fluorescent protein) that allow islet beta cell metabolism and Ca 2+ handling to be imaged in situ in the intact islet with single cell resolution. Combined with classical biochemistry, these techniques show that the beta cell is uniquely poised, thanks to the expression of low levels of lactate dehydrogenase and plasma membrane lactate/monocarboxylate transporters, to channel glucose carbons towards oxidative metabolism, ATP synthesis and inhibition of AMP-activated protein kinase, a newly defined regulator of insulin release. I also discuss the molecular basis of the recruitment of secretory vesicles to the cell surface, analysed by the use of new imaging techniques including total internal reflection of fluorescence, as well as the "nanomechanics" of the exocytotic event itself.

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Section: Introductionmentioning

confidence: 99%

Visualising insulin secretion. The Minkowski Lecture 2004

Rutter

2004

Diabetologia

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“…In cultured hepatoma cells, insulin rapidly leads to the activation of ACC. This activation is accompanied by inhibition of 5h-AMP-activated protein kinase [11], which is described as the major regulator of ACC [12][13][14]. In contrast, glucagon treatment of the cells produces further inactivation of the enzyme as the result of phosphorylation of ACC by the 5h-AMP-activated protein kinase [15].…”

Section: Introductionmentioning

confidence: 99%

Cloning and characterization of the 5′ end and promoter region of the chicken acetyl-CoA carboxylase gene

Mounier

Fur

Powell

et al. 1996

Biochemical Journal

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Acetyl-CoA carboxylase is a rate-limiting enzyme in the biogenesis of long-chain fatty acids. In the present study, the 5h end and flanking region of the acetyl-CoA carboxylase (ACC) gene was analysed in the chicken. A genomic clone was isolated containing the first three exons, the third one containing the ATG codon. Using nuclease-mapping experiments and primerextension analyses, the transcription-initiation site was located 153 nucleotides upstream of the ATG codon. In contrast with rat ACC gene expression, reverse transcriptase PCR analysis performed on chicken liver mRNA did not reveal alternative splicing in the 5h-untranslated region of these messengers. The promoter

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“…LKB1/AMPK signaling induces several cellular processes, one of which is the control of energy metabolism through regulation of several downstream targets, including the metabolic enzymes acetyl-CoA carboxylase and HMG-CoA reductase (Figure 2) (Carling et al, 1987). By suppressing energy-consuming processes such as glycogen and lipid synthesis on the one hand, and enhancing energy-gaining pathways such as glycolysis on the other, AMPK activation aids in restoration of the cellular energy status (Kola et al, 2006).…”

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confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis

Cited by 530 publications

References 25 publications

Visualising insulin secretion. The Minkowski Lecture 2004

Visualising insulin secretion. The Minkowski Lecture 2004

Cloning and characterization of the 5′ end and promoter region of the chicken acetyl-CoA carboxylase gene

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

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