title: Elevated ATF4 expression, in the absence of other signals, is sufficient for transcriptional induction via CCAAT enhancer-binding protein-activating transcription factor response elements.
abstract: Protein limitation in vivo or amino acid deprivation of cells in culture causes a signal transduction cascade consisting of activation of the kinase GCN2 (general control nonderepressible 2), phosphorylation of eukaryotic initiation factor 2, and increased synthesis of activating transcription factor (ATF) 4 by a translational control mechanism. In a self-limiting transcriptional program, ATF4 transiently activates a wide range of downstream target genes involved in transport, cellular metabolism, and other cell functions. Simultaneous activation of other signal transduction pathways by amino acid deprivation led to the question of whether or not the increased abundance of ATF4 alone was sufficient to trigger the transcriptional control mechanisms. Using 293 cells that ectopically express ATF4 in a tetracycline-inducible manner showed that ATF4 target genes were activated in the absence of amino acid deprivation. Ectopic expression of ATF4 alone resulted in effective recruitment of the general transcription machinery, but some reduction in histone modification was observed. These data document that ATF4 alone is sufficient to trigger the amino acid-responsive transcriptional control program. However, the absolute amount of ectopic ATF4 required to achieve the same degree of transcriptional activation observed after amino acid limitation was greater, suggesting that other factors may serve to enhance ATF4 function.
authors.affiliation: Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.forename: Daima
authors.initials: D
authors.lastname: Ord
authors.forename: Tõnis
authors.initials: T
authors.lastname: Ord
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000737:chemistry; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D014176:Protein Biosynthesis; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D000596:Amino Acids; D022762:CCAAT-Enhancer-Binding Proteins; D006657:Histones; D051701:Activating Transcription Factor 4