Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M et al.. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9: 218-224

Department of Molecular Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Nature Cell Biology (Impact Factor: 19.68). 03/2007; 9(2):218-24. DOI: 10.1038/ncb1537
Source: PubMed


Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells. We present evidence that the cyclin-dependent kinase inhibitor p27(Kip1), is phosphorylated at Thr 198 downstream of the Peutz-Jeghers syndrome protein-AMP-activated protein kinase (LKB1-AMPK) energy-sensing pathway, thereby increasing p27 stability and directly linking sensing of nutrient concentration and bioenergetics to cell-cycle progression. Ectopic expression of wild-type and phosphomimetic Thr 198 to Asp 198 (T198D), but not unstable Thr 198 to Ala 198 (p27(T198A)) is sufficient to induce autophagy. Under stress conditions that activate the LKB1-AMPK pathway with subsequent induction of autophagy, p27 knockdown results in apoptosis. Thus LKB1-AMPK pathway-dependent phosphorylation of p27 at Thr 198 stabilizes p27 and permits cells to survive growth factor withdrawal and metabolic stress through autophagy. This may contribute to tumour-cell survival under conditions of growth factor deprivation, disrupted nutrient and energy metabolism, or during stress of chemotherapy.

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    • "For example, as revealed in experiment [8], if the rate of autolysosome formation exceeds that of autophagosome formation, the steady-state concentration of autophagosomes could be detected less, leading to an underestimation of the autophagy status. Moreover, the autophagic process is regulated by the complex positive–negative feedback mechanism (see Figure 1): The output of the process, i.e., recycled amino acids and ATP, acts as the input of the system, which independently manipulates each of the steps in a concentration-dependent manner [9-14]. Such feedback loops may be beneficial for the delicate balance of the cellular homeostasis. "
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    ABSTRACT: Background A number of cellular- and molecular-level studies of autophagy assessment have been carried out with the help of various biochemical and morphological indices. Still there exists ambiguity for the assessment of the autophagy status and of the causal relationship between autophagy and related cellular changes. To circumvent such difficulties, we probe new quantitative indices of autophagy which are important for defining autophagy activation and further assessing its roles associated with different physiopathological states. Methods Our approach is based on the minimal autophagy model that allows us to understand underlying dynamics of autophagy from biological experiments. Specifically, based on the model, we reconstruct the experimental context-specific autophagy profiles from the target autophagy system, and two quantitative indices are defined from the model-driven profiles. The indices are then applied to the simulation-based analysis, for the specific and quantitative interpretation of the system. Results Two quantitative indices measuring autophagy activities in the induction of sequestration fluxes and in the selective degradation are proposed, based on the model-driven autophagy profiles such as the time evolution of autophagy fluxes, levels of autophagosomes/autolysosomes, and corresponding cellular changes. Further, with the help of the indices, those biological experiments of the target autophagy system have been successfully analyzed, implying that the indices are useful not only for defining autophagy activation but also for assessing its role in a specific and quantitative manner. Conclusions Such quantitative autophagy indices in conjunction with the computer-aided analysis should provide new opportunities to characterize the causal relationship between autophagy activity and the corresponding cellular change, based on the system-level understanding of the autophagic process at good time resolution, complementing the current in vivo and in vitro assays.
    Theoretical Biology and Medical Modelling 07/2014; 11(1):31. DOI:10.1186/1742-4682-11-31 · 0.95 Impact Factor
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    • "Through these processes, cells can remove malfunctioning proteins and extend its lifespan. Autophagy can be regulated through mammalian target of rapamycin (mTOR) signaling pathway, and also can be upregulated by AMP-activated protein kinase (AMPK) and beclin-1 (Larsen and Sulzer, 2002; Hay and Sonenberg, 2004; Liang et al., 2007; Shin et al., 2011). "
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    ABSTRACT: Autophagy is a series of catabolic process mediating the bulk degradation of intracellular proteins and organelles through formation of a double-membrane vesicle, known as an autophagosome, and fusing with lysosome. Autophagy plays an important role of death-survival decisions in neuronal cells, which may influence to several neurodegenerative disorders including Parkinson's disease. Chebulagic acid, the major constituent of Terminalia chebula and Phyllanthus emblica, is a benzopyran tannin compound with various kinds of beneficial effects. This study was performed to investigate the autophagy enhancing effect of chebulagic acid on human neuroblastoma SH-SY5Y cell lines. We determined the effect of chebulagic acid on expression levels of autophago-some marker proteins such as, DOR/TP53INP2, Golgi-associated ATPase Enhancer of 16 kDa (GATE 16) and Light chain 3 II (LC3 II), as well as those of its upstream pathway proteins, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and Beclin-1. All of those proteins were modulated by chebulagic acid treatment in a way of enhancing the autophagy. Additionally in our study, chebulagic acid also showed a protective effect against 1-methyl-4-phenylpyridinium (MPP(+)) - induced cytotoxicity which mimics the pathological symptom of Parkinson's disease. This effect seems partially mediated by enhanced autophagy which increased the degradation of aggregated or misfolded proteins from cells. This study suggests that chebulagic acid is an attractive candidate as an autophagy-enhancing agent and therefore, it may provide a promising strategy to prevent or cure the diseases caused by accumulation of abnormal proteins including Parkinson's disease.
    Biomolecules and Therapeutics 07/2014; 22(4):275-81. DOI:10.4062/biomolther.2014.068 · 1.73 Impact Factor
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    • "A . J . Meijer et al . by us ( Meley et al . 2006 ) and later by others ( Hoyer - Hansen et al . 2007 ; Liang et al . 2007 ) , that AMPK is essential for autophagy . The activation of AMPK also underlied the stimulation of autophagy in cerebral ( Adhami et al . 2006 ) and cardiac ischemia ( Matsui et al . 2007 ) ."
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    ABSTRACT: Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.
    Amino Acids 06/2014; 47(10). DOI:10.1007/s00726-014-1765-4 · 3.29 Impact Factor
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