Autophagy and signaling: Their role in cell survival and cell death

1INSERM U504, Glycobiologie et Signalisation cellulaire, Institut André Lwoff, 16 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France.
Cell Death and Differentiation (Impact Factor: 8.18). 12/2005; 12 Suppl 2(Suppl 2):1509-18. DOI: 10.1038/sj.cdd.4401751
Source: PubMed


Macroautophagy is a vacuolar, self-digesting mechanism responsible for the removal of long-lived proteins and damaged organelles by the lysosome. The discovery of the ATG genes has provided key information about the formation of the autophagosome, and about the role of macroautophagy in allowing cells to survive during nutrient depletion and/or in the absence of growth factors. Two connected signaling pathways encompassing class-I phosphatidylinositol 3-kinase and (mammalian) target of rapamycin play a central role in controlling macroautophagy in response to starvation. However, a considerable body of literature reports that macroautophagy is also a cell death mechanism that can occur either in the absence of detectable signs of apoptosis (via autophagic cell death) or concomitantly with apoptosis. Macroautophagy is activated by signaling pathways that also control apoptosis. The aim of this review is to discuss the signaling pathways that control macroautophagy during cell survival and cell death.

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Available from: Alfred J Meijer,
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    • "The autophagy signaling, which constitutes the second pathway, is important for maintain‐ ing cell metabolism and organelle turnover. It involves the degradation of substrates by hydrolases into a vesicle called lysosome [18]. Recent evidence demonstrates cross talk and cooperation between the ubiquitin-proteasome system and autophagy [19] [20]. "
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    ABSTRACT: Autophagy is an evolutionarily conserved intracellular system that selectively eliminates protein aggregates, damaged organelles, and other cellular debris. It is a self-cleaning process critical for cell homeostasis in conditions of energy stress. Autophagy has been until now relatively overlooked in skeletal muscle, but recent data highlight its vital role in this tissue in response to several stress conditions. The most recognized sensors for autophagy modulation are the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and the mechanistic target of rapamycin (MTOR). AMPK acts as a sensor of cellular energy status by regulating several intracellular systems including glucose and lipid metabolisms and mitochondrial biogenesis. Recently, AMPK has been involved in the control of protein synthesis by decreasing MTOR activity and in the control of protein breakdown programs. Concerning proteolysis, AMPK notably regulates autophagy through FoxO transcription factors and Ulk1 complex. In this chapter, we describe the functioning of the different autophagy pathways (macroautophagy, microautophagy, and chaperone-mediated autophagy) in skeletal muscle and define the role of macroautophagy in response to physical exercise, a stress that is well assumed to be a key strategy to counteract metabolic and muscle diseases. The effects of dietary factors and altitude exposure are also discussed in the context of exercise.
    Muscle Cell and Tissue, Edited by Kunihiro Sakuma, 09/2015: chapter 7; Intek., ISBN: 978-953-51-2156-5
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    • "Autophagy is another feature of senescent cells which can also be initiated by DNA damage and promote cell survival (Rodriguez-Rocha et al. 2011, Singh et al. 2012). Autophagy promotes cell survival by the degradation of damaged cellular components (Codogno and Meijer, 2005), probably as a result of elevated ROS (Scherz-Shouval and Elazar, 2011) in the case of cell senescence. "
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    ABSTRACT: Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a pro-inflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, well-established triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established “atypical” senescent states that may occur independent of DNA damage.
    Age 03/2015; DOI:10.1007/s11357-015-9764-2 · 3.45 Impact Factor
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    • "In addition, autophagy can also be stimulated in response to different conditions of stress such as starvation, hypoxia, oxidative stress, drug treatment or DNA damage (He and Klionsky, 2009). In both cases, autophagy represents a pro-survival mechanism allowing quality control, metabolic reprogramming or cell fitness after a stress (Semenza, 2010; Mehrpour et al., 2010; Codogno and Meijer, 2005; Shannon et al., 2003; Brahimi-Horn and Pouyssegur, 2006). Moreover, evidence that autophagy plays a role in maintaining cancer cell survival in their microenvironment where nutrients and oxygen are reduced or in response to anticancer chemotherapies have been reported (Notte et al., 2013; Checinska and Soengas, 2011; Notte et al., 2011; Morselli et al., 2009; Shen et al., 2012; White, 2012; Song et al., 2009; Zhang et al., 2008). "
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    ABSTRACT: Understanding the mechanisms responsible for the resistance against chemotherapy-induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation are known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anti-cancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA-MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxol-induced UPR activation differently according to the different UPR pathways (PERK, ATF6 and IRE1α). The putative involvement of these signalling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, that occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxol-induced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors. Copyright © 2015. Published by Elsevier Ltd.
    The International Journal of Biochemistry & Cell Biology 02/2015; 62. DOI:10.1016/j.biocel.2015.02.010 · 4.05 Impact Factor
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