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Regulated translation initiation controls stress-induced gene expression in mammalian cells.
Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis, resulting in the induction of the downstream gene CHOP (GADD153). Expand
Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells.
  • K. Vattem, R. Wek
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences…
  • 3 August 2004
The results suggest that the mechanism of translation reinitiation involving uORFs is conserved from yeast to mammals. Expand
Coping with stress: eIF2 kinases and translational control.
While many of the genes induced by eIF2 phosphorylation are shared between different environmental stresses, eIF1 kinases function in conjunction with other stress-response pathways, such as those regulated by mitogen-activated protein kinases, to elicit gene expression programmes that are tailored for the specific stress condition. Expand
Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response
Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. Expand
Identification and Characterization of Pancreatic Eukaryotic Initiation Factor 2 α-Subunit Kinase, PEK, Involved in Translational Control
  • Yuguang Shi, K. Vattem, +4 authors R. Wek
  • Medicine, Biology
  • Molecular and Cellular Biology
  • 1 December 1998
Using recombinant PEK produced inEscherichia coli or Sf-9 insect cells, it is demonstrated that PEK is autophosphorylated on both serine and threonine residues and that the recombinant enzyme can specifically phosphorylate eIF-2α on serine-51. Expand
Phosphorylation of eIF2 Facilitates Ribosomal Bypass of an Inhibitory Upstream ORF to Enhance CHOP Translation*♦
It is shown that eIF2 phosphorylation induces preferential translation of CHOP by a mechanism involving a single upstream ORF (uORF) located in the 5′-leader of the CHOP mRNA, which explains how expression ofCHOP and the fate of cells are tightly linked to the levels of phosphorylated eif2 and stress damage. Expand
Phosphorylation of initiation factor 2α by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast
An established mechanism for regulating total protein synthesis in mammalian cells mediates gene-specific translational control in yeast through phosphorylation of the alpha subunit of eIF-2 by the protein kinase GCN2. Expand
The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids
These in vivo and in vitro experiments indicate that synthetase-related sequences regulate GCN2 kinase function by monitoring the levels of multiple uncharged tRNAs that accumulate during amino acid limitations. Expand
Phosphorylation of eIF2 Directs ATF5 Translational Control in Response to Diverse Stress Conditions*
It is shown that the expression of the basic zipper transcriptional regulator ATF5 is induced in response to many different stresses, including endoplasmic reticulum stress, arsenite exposure, and proteasome inhibition, by a mechanism requiring eIF2 phosphorylation. Expand
Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses.
It is suggested that eIF2alpha kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIFalpha phosphorylation is central to activation of the NF-kappaB. Expand