The roles of translation initiation regulation in ultraviolet light-induced apoptosis

Parker, Suzanne H.; Parker, Todd; George, Kimberly S.; Wu, Shiyong

doi:10.1007/s11010-006-9239-y

Cited by 19 publications

(19 citation statements)

References 44 publications

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“…We also observed that, in PERK knockdown G401 cells and mPERK knockdown MEF cells, similar to the findings in HeLa cells, SubAB-induced caspase-7 activation was inhibited. There are cases in which PERK activation promotes or protects against ER stress-induced apoptosis (11,19,22,36). These studies imply that PERK plays different roles in regulation of cell proliferation or apoptosis, depending on the cell type or species.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous data showed that after treatment of cells with SubAB, protein synthesis was transiently suppressed for 2 h and then moderately recovered; these events were probably regulated by a pathway downstream of eIF2␣ phosphorylation (30). A recent study showed that eIF2␣ kinases may mediate UV light-induced apoptosis via eIF2␣-dependent or -independent signaling pathways (36). In contrast, studies of ␤-amyloid (A␤)-mediated cell death in SK-N-SH human neuroblastoma cells demonstrated that maintaining levels of phosphorylation of eIF2␣ inhibited cell death (22).…”

Section: Figmentioning

confidence: 99%

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Regulation of Subtilase Cytotoxin-Induced Cell Death by an RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase-Dependent Proteasome Pathway in HeLa Cells

et al. 2012

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c Shiga-toxigenic Escherichia coli (STEC) produces subtilase cytotoxin (SubAB), which cleaves the molecular chaperone BiP in the endoplasmic reticulum (ER), leading to an ER stress response and then activation of apoptotic signaling pathways. Here, we show that an early event in SubAB-induced apoptosis in HeLa cells is mediated by RNA-dependent protein kinase (PKR)-like ER kinase (PERK), not activating transcription factor 6 (ATF6) or inositol-requiring enzyme 1(Ire1), two other ER stress sensors. PERK knockdown suppressed SubAB-induced eIF2␣ phosphorylation, activating transcription factor 4 (ATF4) expression, caspase activation, and cytotoxicity. Knockdown of eIF2␣ by small interfering RNA (siRNA) or inhibition of eIF2␣ dephosphorylation by Sal003 enhanced SubAB-induced caspase activation. Treatment with proteasome inhibitors (i.e., MG132 and lactacystin), but not a general caspase inhibitor (Z-VAD) or a lysosome inhibitor (chloroquine), suppressed SubAB-induced caspase activation and poly(ADP-ribose) polymerase (PARP) cleavage, suggesting that the ubiquitin-proteasome system controls events leading to caspase activation, i.e., Bax/Bak conformational changes, followed by cytochrome c release from mitochondria. Levels of ubiquitinated proteins in HeLa cells were significantly decreased by SubAB treatment. Further, in an early event, some antiapoptotic proteins, which normally turn over rapidly, have their synthesis inhibited, and show enhanced degradation via the proteasome, resulting in apoptosis. In PERK knockdown cells, SubAB-induced loss of ubiquitinated proteins was inhibited. Thus, SubAB-induced ER stress is caused by BiP cleavage, leading to PERK activation, not by accumulation of ubiquitinated proteins, which undergo PERK-dependent degradation via the ubiquitin-proteasome system.

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Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Regulation of Subtilase Cytotoxin-Induced Cell Death by an RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase-Dependent Proteasome Pathway in HeLa Cells

et al. 2012

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“…Although the roles of PERK and GCN2 in UV-induced translation inhibition and downstream signal transduction have been previously elucidated (2,4,28), their key activators have not been identified. We now demonstrate that UVB-induced translational inhibition in cultured human skin cells is, at least partially, mediated by NOS-catalyzed NO ⅐ production in combination with superoxide production.…”

Section: Discussionmentioning

confidence: 99%

The Role of Nitric-oxide Synthase in the Regulation of UVB Light-induced Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2

Lü

László

Miao³

et al. 2009

Journal of Biological Chemistry

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UV light induces phosphorylation of the ␣ subunit of the eukaryotic initiation factor 2 (eIF2␣) and inhibits global protein synthesis. Both eIF2 kinases, protein kinase-like endoplasmic reticulum kinase (PERK) and general control of nonderepressible protein kinase 2 (GCN2), have been shown to phosphorylate eIF2␣ in response to UV irradiation. However, the roles of PERK and GCN2 in UV-induced eIF2␣ phosphorylation are controversial. The one or more upstream signaling pathways that lead to the activation of PERK or GCN2 remain unknown. In this report we provide data showing that both PERK and GCN2 contribute to UV-induced eIF2␣ phosphorylation in human keratinocyte (HaCaT) and mouse embryonic fibroblast cells. Reduction of expression of PERK or GCN2 by small interfering RNA decreases phosphorylation of eIF2␣ after UV irradiation. These data also show that nitric-oxide synthase (NOS)-mediated oxidative stress plays a role in regulation of eIF2␣ phosphorylation upon UV irradiation. Treating the cells with the broad NOS inhibitor N G -methyl-L-arginine, the free radical scavenger N-acetyl-L-cysteine, or the NOS substrate L-arginine partially inhibits UV-induced eIF2␣ phosphorylation. The results presented above led us to propose that NOS mediates UV-induced eIF2␣ phosphorylation by activation of both PERK and GCN2 via oxidative stress and L-arginine starvation signaling pathways.UV irradiation inhibits translation initiation through activation of kinases that phosphorylate the ␣-subunit of eukaryotic initiation factor 2 (eIF2␣).2 Two eIF2␣ kinases, double strand RNA-dependent protein kinase-like ER kinase (PERK) and general control of amino acid biosynthesis kinase (GCN2), are known to phosphorylate the serine 51 of eIF2␣ in response to UV irradiation (1-4). However, the one or more upstream pathways that activate eIF2␣ kinase(s) upon UV irradiation are not known. In this report, we provide evidence that UV-induced nitric-oxide synthase (NOS) activation and nitric oxide (NO ⅐ ) production regulate both PERK and GCN2 activation upon UVB irradiation.Expression of inducible nitric-oxide synthase in a mouse macrophage cell line leads to the phosphorylation of eIF2␣ and inhibition of translation (5). In cultured neuronal and pancreatic cell lines, production of NO ⅐ and peroxynitrite (ONOO Ϫ ) induces endoplasmic reticulum (ER) stress, which activates PERK and results in cell dysfunction and apoptosis (6 -9). Cytokine-stimulated inducible nitric-oxide synthase activation in astrocytes depletes L-arginine and activates GCN2, which phosphorylates eIF2␣ (10). UV irradiation also activates NOS and elevates cellular NO ⅐ (11-13). However, the UV-induced NOS activation and NO ⅐ production have never been shown to be related to the activation of eIF2␣ kinase(s). Now we demonstrate that UV-induced activation of NOS mediates the activation of both PERK and GCN2, which coordinately regulate the phosphorylation of eIF2␣. EXPERIMENTAL PROCEDURESCell Culture-HaCaT cells (kindly provided by Dr. Hongtao Yu, Jackson State University) wer...

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“…However, recent studies have demonstrated the role played by GCN2 in other cellular responses, such as sensitivity to RNA viral infection 5 or T-cell differentiation. 6 Although GCN2 is typically activated by amino acid deprivation, UV exposure 7,8 or high levels of urea 9 can also lead to GCN2 activation. These data suggest that GCN2 could act as a key regulator to the cellular response under stress conditions.…”

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confidence: 99%

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Arriazu

López-Zabalza

Leung

et al. 2013

Laboratory Investigation

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General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knockout mice (Gcn2 À / À ) showed increased susceptibility to both acute or chronic liver damage induced by CCl 4 , as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl 4 treatment increased deposition of interstitial collagen type I more in Gcn2 À / À mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl 4 -treated Gcn2 À / À mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

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The roles of translation initiation regulation in ultraviolet light-induced apoptosis

Cited by 19 publications

References 44 publications

Regulation of Subtilase Cytotoxin-Induced Cell Death by an RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase-Dependent Proteasome Pathway in HeLa Cells

Regulation of Subtilase Cytotoxin-Induced Cell Death by an RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase-Dependent Proteasome Pathway in HeLa Cells

The Role of Nitric-oxide Synthase in the Regulation of UVB Light-induced Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

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