A Genome-Wide siRNA Screen Reveals Multiple mTORC1 Independent Signaling Pathways Regulating Autophagy under Normal Nutritional Conditions

Lipinski, Marta M.; Hoffman, Greg; Ng, Aylwin; Zhou, Wen; Py, Bénédicte F.; Hsu, Emily; Liu, Xuxin; Eisenberg, Jason M.; Li, Jun; Blenis, John; Xavier, Ramnik J.; Yuan, Junying

doi:10.1016/j.devcel.2010.05.005

Cited by 206 publications

(192 citation statements)

References 34 publications

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“…Activation of mTOR by these transforming events (Shaw and Cantley, 2006;Ravitz et al, 2007) is one mechanism by which autophagy might be downregulated in response to oncogenic signaling. Cytokine receptor engagement also triggers signaling events that suppress autophagy (Lipinski et al, 2010). These studies support the hypothesis that certain early drivers of transformation suppress autophagy, perhaps to accommodate the need for a rapid increase in cell mass to fuel cell proliferation.…”

Section: Effects Of Metabolic Reprogramming On Autophagy: Glycolysissupporting

confidence: 61%

“…Amino-acid regulation of autophagy also occurs in an mTOR-independent manner in muscle cells (Mordier et al, 2000) through FoxO3-mediated transcription of the autophagy genes MAP1LC3B (microtubule-associated protein 1 light chain 3 b) and BNIP3 (BCL2/ adenovirus E1B 19 kDa protein-interacting protein 3) (Mammucari et al, 2007), and in liver cells (Kanazawa et al, 2004). A small interfering RNA screen for autophagy modulators also identified a number of growth factors and cytokines that suppress autophagy independently of mTOR through inhibition of class-III PI3K (Lipinski et al, 2010).…”

Section: Physiological Control Of Autophagy: Mtormentioning

confidence: 99%

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The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

Eng

Abraham

2011

Oncogene

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Tumorigenesis is often accompanied by metabolic changes that favor rapid energy production and increased biosynthetic capabilities. These metabolic adaptations promote the survival and proliferation of tumor cells, and in conjunction with the hypoxic and metabolically challenged tumor microenvironment, influence autophagic activity. Autophagy is a catabolic process that allows cellular macromolecules to be broken down and re-utilized as metabolic precursors. Stimulation of autophagy promotes the survival of tumor cells under stressful metabolic and environmental conditions, and counters the potentially deleterious effects of mitochondrial dysfunction and the ROS that these organelles generate. However, inhibition of autophagy has also been reported to fuel tumorigenesis. In spite of the advances in our understanding of the relationship between autophagy and tumorigenesis, it remains unclear whether the therapeutic approaches targeting autophagy should aim to increase or decrease autophagic flux in tumor tissues in human patients. Here, we review how metabolic reprogramming influences autophagic activity in tumors, and discuss how inhibition of autophagy might be exploited to target tumor cells that show altered metabolism.

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Section: Effects Of Metabolic Reprogramming On Autophagy: Glycolysissupporting

confidence: 61%

Section: Physiological Control Of Autophagy: Mtormentioning

confidence: 99%

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

Eng

Abraham

2011

Oncogene

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“…The etiology of Huntington and taupathies involves protein accumulation in the nervous system. However, TOR-independent routes of autophagy exist (Lipinski et al, 2010).…”

Section: Cyclic Illumination Causes Additional Stress and Induces Autmentioning

confidence: 99%

Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina

et al. 2014

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Abbreviations: AMD, age-related macular degeneration; BSA, bovine serum albumin; CHOP, C/EBP homology protein; CtBP2, C-terminal binding protein 2; ER, endoplasmic reticulum; GRP78/BiP, glucoseregulated protein 78kDa/Binding immunoglobulin protein, INL, inner nuclear layer; IPL, inner plexiform layer; LC3B, microtubule-associated protein light chain 3B; mTOR, mammalian target of rapamycin; ONL, outer nuclear layer; OPL, outer nuclear layer; PBS, phosphate buffered saline; PNA, peanut agglutinin; p62/SQSTM1; nucleoporin p62/sequestosom 1; PSD-95, postsynaptic density protein 95; rd1, retinal degeneration 1; RPE, retinal pigment epithelium; UPS, ubiquitin-proteasome system; 2 AbstractThe aim of this study was to investigate rod and cone photoreceptor degeneration in organotypic cultures of adult porcine retina. Our hypothesis was that the photoreceptors accumulate opsins, which, together with exposure to cyclic dim light illumination, induce autophagy and endoplasmic reticulum stress (ER-stress) to overcome damaging protein overload. For this purpose, retinas were cultured for 48 h and 72 h during which they were illuminated with dim light for 8 h/day; specimens were analyzed by means of immunohistochemistry, western blot and transmission electron microscopy. ER-stress and photoreceptor degeneration was observed in conventionally cultured retinas. The additional stress in the form of dim light illumination for 8 h/day resulted in increased levels of the ER-stress markers GRP78/BiP and CHOP, as well as increased level of active caspase-12. Increased autophagic processes in cone and rod photoreceptors were detected by LC3B-II increases and occurrence of autophagosomes at the ultrastructural level. Illumination also resulted in altered protein expression for autophagy inducers such as p62 and Beclin-1. Moreover, there was a decrease in phosphorylated mammalian target of rapamycin (mTOR), which further indicate an increase of autophagy. Rod and cone photoreceptors in retinas from a diurnal animal that were exposed to dim light illumination in vitro displayed autophagy and ER-stress processes. In particular, these processes resulted in decreased protein levels for rhodopsin.3

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“…Beyond ultrastructural analyses, one of the most effective methods to detect autophagosomes and autophagolysosomes consists of the transfection-enforced expression of a green fluorescent protein (GFP)-LC3 fusion protein that decorates the membranes of autophago(lyso)somes, both in vivo, in animals , or in vitro, in cultured cells (Kabeya et al, 2000), including in high-content screens (Zhang et al, 2007;Lipinski et al, 2010). GFP-LC3 usually distributes diffusely throughout cells, yet accumulates in so-called 'autophagic puncta' (Kabeya et al, 2000) in the cytoplasm of cells when autophagy is induced.…”

Section: Introductionmentioning

confidence: 99%

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

et al. 2011

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To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a highcontent screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to B1400 compounds. Many agents induced a 'pure' autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.

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A Genome-Wide siRNA Screen Reveals Multiple mTORC1 Independent Signaling Pathways Regulating Autophagy under Normal Nutritional Conditions

Cited by 206 publications

References 34 publications

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

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