Direct Induction of Autophagy by Atg1 Inhibits Cell Growth and Induces Apoptotic Cell Death

Scott, Rebecca J.; Juhász, Gábor; Neufeld, Thomas P.

doi:10.1016/j.cub.2006.10.053

Cited by 655 publications

(797 citation statements)

References 47 publications

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“…Although cytoprotective and cytotoxic roles have been ascribed to ULK1's autophagic function, 21,23,46 our results provide evidence that ULK1 acts as a prodeath molecule in an Atg7-independent manner. In Drosophila, overexpression of Atg1 promotes cell death through an apoptotic pathway, 47 whereas in human osteosarcoma cells treated with camptothecin the p53-dependent upregulation of ULK1 potentiates cell death. 21 Our results indicate that ULK1 is one of several ATG proteins that induces cell death through autophagy-independent pathways.…”

Section: Discussionmentioning

confidence: 99%

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

et al. 2015

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Reactive oxygen species (ROS) may cause cellular damage and oxidative stress-induced cell death. Autophagy, an evolutionarily conserved intracellular catabolic process, is executed by autophagy (ATG) proteins, including the autophagy initiation kinase Unc-51-like kinase (ULK1)/ATG1. Although autophagy has been implicated to have both cytoprotective and cytotoxic roles in the response to ROS, the role of individual ATG proteins, including ULK1, remains poorly characterized. In this study, we demonstrate that ULK1 sensitizes cells to necrotic cell death induced by hydrogen peroxide (H 2 O 2 ). Moreover, we demonstrate that ULK1 localizes to the nucleus and regulates the activity of the DNA damage repair protein poly (ADP-ribose) polymerase 1 (PARP1) in a kinase-dependent manner. By enhancing PARP1 activity, ULK1 contributes to ATP depletion and death of H 2 O 2 -treated cells. Our study provides the first evidence of an autophagy-independent prodeath role for nuclear ULK1 in response to ROS-induced damage. On the basis of our data, we propose that the subcellular distribution of ULK1 has an important role in deciding whether a cell lives or dies on exposure to adverse environmental or intracellular conditions. Cell Death and Differentiation (2016) 23, 216-230; doi:10.1038/cdd.2015; published online 3 July 2015Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide (H 2 O 2 ), are formed by the incomplete reduction of oxygen during oxidative phosphorylation and other enzymatic processes. ROS are signaling molecules that regulate cell proliferation, differentiation, and survival. 1-3 Accumulation of ROS (i.e., oxidative stress) on exposure to xenobiotic agents or environmental toxins can cause cellular damage and death via apoptotic or nonapoptotic pathways. [4][5][6] Oxidative stress-induced cellular damage and death have been implicated in aging, ischemia-reperfusion injury, inflammation, and the pathogenesis of diseases (e.g., neurodegeneration and cancer). 7 Oxidative stress also contributes to the antitumor effects of many chemotherapeutic drugs, including camptothecin 8,9 and selenite. 10,11 Autophagy, an evolutionarily conserved intracellular catabolic process, involves lysosome-dependent degradation of superfluous and damaged cytosolic organelles and proteins. 12 It is typically upregulated under conditions of perceived stress and in response to cellular damage. The consequence of autophagy activation -whether cytoprotective or cytotoxicappears to depend on the cell type and the nature and extent of stress. Although most studies indicate a cytoprotective role for autophagy, some evidence suggests that it contributes to cell death in response to oxidative stress. [13][14][15][16][17] Studies have also indicated that autophagy may be suppressed in response to oxidative stress, thereby sensitizing certain cells to apoptosis. 18,19 Unc-51-like kinase/autophagy 1 (ULK1/ATG1) is a mammalian serine-threonine kinase that regulates flux through the autophagy pathway by activating the VPS34 PI(3) kinas...

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Section: Discussionmentioning

confidence: 99%

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

et al. 2015

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“…For example, the disaccharide trehalose is an mTOR-independent activator of autophagy (30). The induction of autophagy occurs through a mechanism that involves the Atg1 kinase, which when overexpressed in Drosophila is sufficient to induce autophagy (31). In mammalian cells the Atg1 ortholog ULK1 also controls autophagy (32).…”

Section: Regulation Of Autophagymentioning

confidence: 99%

“…Neufeld and colleagues performed experiments to overexpress Atg1 in Drosophila and found that this was sufficient to increase autophagy, to inhibit cell growth and to induce cell death (31). However, while the death required that the autophagy signal from Atg1 be propagatedmutation of a downstream autophagy regulator, Atg8 blocked the Atg1-induced death-the actual mechanism of cell death appeared to be through apoptosis and was associated with increased caspase activity and blocked by a caspase inhibitor.…”

Section: Are Autophagic and Apoptotic Cell Death Different Facets Of mentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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“…In Drosophila, enforced ATG1 expression induces excessive autophagy, resulting in apoptosis [16]. Similarly, destruction of the fly larval salivary gland involves massive autophagy and ATGs are required for this developmental cell death [17].…”

Section: Autophagy and Cell Fatementioning

confidence: 99%

Extracellular matrix regulation of autophagy

Lock

Debnath

2008

Current Opinion in Cell Biology

158

136

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SummaryIntegrin-mediated attachment of epithelial cells to extracellular matrix (ECM) is critical for proper growth and survival. Although detachment leads to apoptosis, termed anoikis, recent work demonstrates that ECM detachment also robustly induces autophagy, a tightly regulated lysosomal self-digestion process that actually promotes survival. Autophagy presumably protects epithelial cells from the stresses of ECM detachment, allowing them to survive provided they reattach in a timely manner. Currently, the intracellular signals linking integrin engagement to autophagy remain unclear, but certain growth factor, energy-sensing, and stress response pathways represent attractive candidates. Moreover, autophagy may be a previously unrecognized mechanism utilized by detached cancer cells to survive anoikis, which may facilitate tumor cell dormancy, dissemination, and metastasis.

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Direct Induction of Autophagy by Atg1 Inhibits Cell Growth and Induces Apoptotic Cell Death

Cited by 655 publications

References 47 publications

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Extracellular matrix regulation of autophagy

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