title: Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response.
abstract: Mammalian cells respond to amino acid deprivation through multiple signaling pathways referred to as the amino acid response (AAR). Transcription factors mediate the AAR after their activation by several mechanisms; examples include translational control (activating transcription factor 4, ATF4), phosphorylation (p-cJUN), and transcriptional control (ATF3). ATF4 induces ATF3 transcription through a promoter-localized C/EBP-ATF response element (CARE). The present report characterizes an ATF/CRE site upstream of the CARE that also contributes to AAR-induced ATF3 transcription. ATF4 binds to the ATF/CRE and CARE sequences and both are required for a maximal response to ATF4 induction. ATF3, which antagonizes ATF4 and represses its own gene, also exhibited binding activity to the ATF/CRE and CARE sequences. The AAR resulted in elevated total cJUN and p-cJUN protein levels and both forms exhibited binding activity to the ATF/CRE and CARE ATF3 sequences. Knockdown of AAR-enhanced cJUN expression blocked induction of the ATF3 gene and mutation of either the ATF/CRE or the CARE site prevented the cJUN-dependent increase in ATF3-driven luciferase activity. The results indicate that both increased cJUN and the cis-acting ATF/CRE sequence within the ATF3 promoter contribute to the transcriptional activation of the gene during the AAR.
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: Lingchen
authors.initials: L
authors.lastname: Fu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056945:Hep G2 Cells; D006641:Histidinol / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000596:Amino Acids; D022782:CCAAT-Enhancer-Binding Protein-beta; D016755:Proto-Oncogene Proteins c-jun; D051701:Activating Transcription Factor 4; D006641:Histidinol