AMPK: A nutrient and energy sensor that maintains energy homeostasis
Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK. Nature Reviews Molecular Cell Biology
(Impact Factor: 37.81).
03/2012; 13(4):251-62. DOI: 10.1038/nrm3311
AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.
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Available from: David Papadopoli
- "AMPK occupies a central position in the reprogramming of cells to adapt to metabolic stress by promoting catabolism and inhibiting anabolism in order to restore the pool of cellular ATP (Hardie et al., 2012). Specifically, AMPK promotes catabolic reactions, such as lipid oxidation and cellular respiration, and inhibits anabolic processes, such as lipid and protein synthesis (Hardie et al., 2012). AMPK activation induces the expression of PGC-1a, and the AMPK-mediated increase in mitochondrial respiration has been shown to be dependent on PGC-1a in muscle cells (Jä ger et al., 2007). "
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ABSTRACT: Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.
- "These data strongly support the concept that eEF2K is cytoprotective in those nutrient-deprived cancer cells. To assess whether the inhibition of eEF2K promotes cell death by disinhibiting translation elongation, we explored the effect of re-imposing inhibition of protein synthesis using two distinct translation inhibitors, cycloheximide (CHX, which inhibits elongation) and Harringtonine (Harr, which inhibits a late step in translation initiation[28,29]). Each of these compounds restored cell survival in cells that had been starved of glucose and treated with the eEF2K inhibitor JAN-849 (Fig. 1B,C), presumably by inhibiting protein synthesis. "
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ABSTRACT: Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency. Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition. eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied. We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy.
Available from: Ruijin Shao
- "However, only AMPKα has been demonstrated in the endometria of women with PCOS and endometrial cancer  . Furthermore, while hormonal, nutrient, and metabolic stress signals regulate AMPK activation and its activity in multiple peripheral tissues such as liver, skeletal muscle, and adipose tissues   as well as different cancer cells , to our knowledge no studies have investigated any causality between androgen , AR expression, and AMPK activation in the endometrium under physiological and pathological conditions. The aims of the present study, therefore, were to investigate the temporal and spatial expression patterns of AR, p-AMPKα, AMPKα, and Ki67 (a cellular marker for proliferation) in the endometrium of PCOS patients in different phases of the menstrual cycle or with hyperplasia. "
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