Autophagy Controls p38 Activation to Promote Cell Survival under Genotoxic Stress

Qiang, Lei; Wu, Chunli; Ming, Mei; Viollet, Benoı̂t; He, Yu‐Ying

doi:10.1074/jbc.m112.415224

Cited by 95 publications

(96 citation statements)

References 54 publications

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“…Our results are consistent with those of Qiang et al [22], who showed that autophagy-associated decreases in p38 phosphorylation enhances cell survival [22]. p38 activity was also found to be reduced in human SCCs, compared to normal human skin [22]. Moreover, inhibition of p38 signaling was associated with a defect in global genome nucleotide excision repair (GG-NER), a vitally important tumor protective pathway that recognizes and excises UVB-induced CPDs (cyclobutane pyrimidine dimers) and 6-4PPs (pyrimidine (6-4) pyrimidone photoproducts) that would otherwise be mutagenic [36].…”

Section: Discussionsupporting

confidence: 94%

Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation

et al. 2014

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p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage—a primary risk factor for human skin cancers—its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (α/β/γ/δ); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38α, without affecting other isoforms. p38α levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38α in SCC pathogenesis. Genetic and pharmacological inhibition of p38α and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38α deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.

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Section: Discussionsupporting

confidence: 94%

Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation

et al. 2014

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“…74,75,91,93 Thus, we hypothesize that after low doses of DNA damage, autophagy activation by these transcription factors would result in clearance of membrane-permeabilized mitochondria, 94 generation of dNTPs and/or ATP for DNA repair activity, 47,48 degradation of pro-apoptotic proteins such as active caspase 8 95 and elimination of p62, thus preventing p38-hyperactivation. 96 Supporting the role of p53 in autophagy and cell survival, p53 mediates the transcription of parkin, 97 suggesting that p53 could regulate transcription of mitophagy genes in response to genomic damage, thus counterbalancing mitochondrial apoptotic signaling.…”

Section: Parpmentioning

confidence: 99%

“…123 Similarly, MSI-positive colon cancer cells with monoallelic deletions of UVRAG or UVRAG-KD HEK cells did not show reduced autophagy. Indeed, UVRAG participates in an autophagy-independent manner in preventing centrosome overduplication and chromosome missegregation during anaphase 124 as well as Increased apoptosis 96 in endocytic trafficking of EGFR, whose accumulation may enhance growth factor receptor signaling, thus supporting tumor growth. 125 Therefore, an autophagy-centric interpretation must always bear in mind these other functions described for the 'autophagy' genes.…”

Section: Parpmentioning

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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“…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) kinase complex and facilitating ATG9-dependent membrane recycling.…”

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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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Autophagy Controls p38 Activation to Promote Cell Survival under Genotoxic Stress

Cited by 95 publications

References 54 publications

Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation

Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation

Autophagy and genomic integrity

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

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