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The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wounding by proper coordination of reactive oxygen species and amino acids

ABSTRACT: Here we report total RNA seq on wounded and unwounded NTERT WT and GCN2 KO cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171666 | GEO | 2021/10/04

REPOSITORIES: GEO

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The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wounding by proper coordination of reactive oxygen species and amino acids

Project description:The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wounding by proper coordination of reactive oxygen species and amino acids

| PRJNA720474 | ENA

The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

Project description:Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing. Wounding of human keratinocyte monolayers in vitro led to the rapid activation of the eIF2 kinase GCN2. We determined that deletion or pharmacological inhibition of GCN2 significantly delayed collective cell migration and wound closure. Global transcriptomic, biochemical, and cellular analyses indicated that GCN2 is necessary for maintenance of intracellular free amino acids, particularly cysteine, as well as coordination of RAC1-GTP-driven reactive oxygen species (ROS) generation, lamellipodia formation, and focal adhesion dynamics following keratinocyte wounding. In vivo experiments using mice deficient for GCN2 validated the role of the eIF2 kinase during wound healing in intact skin. These results indicate that GCN2 is critical for appropriate induction of collective cell migration and plays a critical role in coordinating the re-epithelialization of cutaneous wounds.

| S-EPMC8554533 | biostudies-literature

Coordination between GCN2 eIF2 kinase and p53 signaling supports purine metabolism and enhances growth and progression of prostate cancer

Project description:Cancers invoke response pathways to mitigate external and internal stresses to aid growth and proliferation. For example, we reported that GCN2 eIF2 kinase and the Integrated Stress Response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, while genetic or pharmacological loss of GCN2 lowers intracellular amino acids and deters PCa growth, there does not appear to be appreciable cell death. Using biochemical and molecular approaches, RNA-seq and CRISPRi-based screens, along with in vitro and in vivo PCa models, we discovered that the loss of GCN2 in PCa induces p53 signaling and tumor senescence. Activation of p53 occurs by reductions in purine nucleobases and lowered rRNA synthesis that induce the Impaired Ribosome Biogenesis Checkpoint. Loss of GCN2 combined with depletion of p53 or pharmacological inhibition of de novo purine biosynthesis with the GART inhibitor pelitrexol sharply reduces PCa growth and triggers apoptosis, emphasizing the importance of coordinated GCN2 and p53 regulation and their utility in PCa therapeutics.

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Selective control of metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae

Project description:When eukaryotic cells are deprived of amino acids, uncharged tRNAs accumulate and activate the conserved GCN2 protein kinase. We examine how yeast growth and tRNA charging or aminoacylation is affected during amino acid depletion in the presence and absence of GCN2. tRNA charging is measured using a microarray technique which allows for simultaneous measurement of all cytosolic tRNAs. A fully prototrophic and its isogenic GCN2 deletion strain were used. We measured relative tRNA charging levels in yeast strains with an intact and deleted GCN2.

2010-08-01 | E-GEOD-22452 | biostudies-arrayexpress

Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions

Project description:Diverse environmental insults induce the integrated stress response (ISR), which features eIF2 phosphorylation and translational control that serves to restore protein homeostasis. The eIF2 kinase GCN2 is a first responder in the ISR that is activated by amino acid depletion and other unrelated stresses. Two processes are suggested to trigger an ordered process of GCN2 activation during stress: GCN2 monitoring stress via accumulating uncharged tRNAs or by stalled and colliding ribosomes. Our results suggest that while ribosomal collisions are indeed essential for GCN2 activation in response to translational elongation inhibitors, conditions that trigger deacylation of tRNAs activate GCN2 via its direct association with affected tRNAs. Both process require the GCN2 regulatory domain related to histidyl tRNA synthetases. GCN2 activation by UV irradiation features lowered amino acids and increased uncharged tRNAs and ribosome collisions are dispensable. We conclude that there are multiple mechanisms that activate GCN2 during diverse stresses.

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Small RNAs from sweet potato upon wounding

Project description:Small RNAs (sRNAs) play important roles in plants encountering stress environments. However, limited research has been conducted on the sRNAs involved in plant wound responses. To identify potential roles for the wounding-related sRNAs, sRNA deep sequencing was used. After leaves were wounded for 0.5 hour, total RNAs from unwounded and wounded leaves were isolated for sRNA library construction. The Illumina platform was used to sequence sRNA libraries. About 12 million sequence reads were obtained for each sample.

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Selective control of metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae

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Project description:Transcriptional profiling of laser wounded syncytial Drosophila embryos compared with control unwounded embryos. Early Drosophila embryos (Nuclear cycle 4-6) were either laser wounded or not wounded, and then collected and processed after 30 minutes. Wounded and unwounded embryos express sGMCA (actin reporter).

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Laser wounded vs unwounded syncytium Drosophila embryos

Project description:Transcriptional profiling of laser wounded syncytial Drosophila embryos compared with control unwounded embryos. Early Drosophila embryos (Nuclear cycle 4-6) were collected, either laser wounded or not wounded, and then collected and processed immediately. Wounded and unwounded embryos express sGMCA (actin reporter)

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