Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death

Gao, Wenhui; Shen, Zhirong; Shang, Libin; Wang, Xiaodong

doi:10.1038/cdd.2011.33

Cited by 156 publications

(132 citation statements)

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“…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. 48 They do not exclude the possibility that ULK1 overexpression promotes apoptosis or autophagy-mediated cell death under certain circumstances but rather provide an alternative mechanism for ULK1-dependent cell death that is associated with nuclear localization of ULK1.…”

Section: Discussionmentioning

confidence: 60%

“…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.…”

Section: Discussionmentioning

confidence: 62%

“…20 Results from two studies suggest that ULK1 expression is altered in response to oxidative stress, and that the corresponding effects on autophagy contribute to cell death. 18,21 For example, p53-mediated upregulation of ULK1 and increase in autophagy promote cell death in osteosarcoma cells exposed to sublethal doses of camptothecin, 21 yet mutant p53-mediated suppression of ULK1 impairs autophagic flux and promotes apoptosis in selenite-treated NB4 cells. 18 Here we investigated the role of ULK1 in cells exposed to H 2 O 2 .…”

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confidence: 99%

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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: 60%

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

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

et al. 2015

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“…p53 can activate autophagy after DNA damage through transcriptional induction of several genes, including damage-regulated autophagy modulator (dram), UNC-51-like kinase 1/2, (ulk1/2), sestrin1/2, isg20L1 and bnip3, among others. 77 p53 targets can regulate autophagy directly, as is the case with the lysosomal proteins DRAM 14 and ULK1/2, which interact with Atg13 and FIP200 to induce autophagy, 13 or indirectly through Sestrin 1 and 2, which activate AMPK and the TSC1/2 complex, leading to inactivation of mTORC1 and autophagy induction. 78 Additionally, ATM was shown to activate AMPK in a p53-independent manner through direct activation of the AMP kinase LKB1.…”

Section: Pathways Connecting Ddr To Autophagymentioning

confidence: 99%

“…[9][10][11] In addition to its role in cell survival, autophagy also contributes to organism homeostasis by clearing apoptotic cells during embryonic development 12 and after certain types of DNA damage. 13,14 In this review, we examine the roles proposed for autophagy in preventing genomic instability, as well as the connection of autophagy to DDR and cell fate after DNA damage. We also discuss the roles proposed for autophagy in the development and therapy of cancer and other human diseases.…”

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confidence: 99%

Autophagy and genomic integrity

et al. 2013

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DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

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Autophagy‐Sensitized Cytotoxicity of Quantum Dots in PC12 Cells

Chen

et al. 2013

Adv Healthcare Materials

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Both CdTe and CdTe/CdS/ZnS quantum dots induce similar levels of autophagy in PC12 and HEK293 cells, while the former exhibits higher toxicity. Low levels of cadmium ions are not sufficient to induce either autophagy or cytotoxicity by themselves. Interestingly, the combination of cadmium ions and CdTe/CdS/ZnS mimics the toxic effect of CdTe, suggesting that autophagy sensitizes cells to cadmium ions.

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Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death

Cited by 156 publications

References 40 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

Autophagy and genomic integrity

Autophagy‐Sensitized Cytotoxicity of Quantum Dots in PC12 Cells

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