title: A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity.
abstract: Alternative splicing and post-translational modifications are processes that give rise to the complexity of the proteome. The nuclear ATF7 and ATF2 (activating transcription factor) are structurally homologous leucine zipper transcription factors encoded by distinct genes. Stress and growth factors activate ATF2 and ATF7 mainly via sequential phosphorylation of two conserved threonine residues in their activation domain. Distinct protein kinases, among which mitogen-activated protein kinases (MAPK), phosphorylate ATF2 and ATF7 first on Thr71/Thr53 and next on Thr69/Thr51 residues respectively, resulting in transcriptional activation. Here, we identify and characterize a cytoplasmic alternatively spliced isoform of ATF7. This variant, named ATF7-4, inhibits both ATF2 and ATF7 transcriptional activities by impairing the first phosphorylation event on Thr71/Thr53 residues. ATF7-4 indeed sequesters the Thr53-phosphorylating kinase in the cytoplasm. Upon stimulus-induced phosphorylation, ATF7-4 is poly-ubiquitinated and degraded, enabling the release of the kinase and ATF7/ATF2 activation. Our data therefore conclusively establish that ATF7-4 is an important cytoplasmic negative regulator of ATF7 and ATF2 transcription factors.
authors.affiliation: Université de Strasbourg, UMR7242 Biotechnologie et Signalisation Cellulaire, Ecole Supérieure de Biotechnologie de Strasbourg, BP10413, Illkirch, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Diring
authors.forename: Barbara
authors.initials: B
authors.lastname: Camuzeaux
authors.forename: Mariel
authors.initials: M
authors.lastname: Donzeau
authors.forename: Marc
authors.initials: M
authors.lastname: Vigneron
authors.forename: Manuel
authors.initials: M
authors.lastname: Rosa-Calatrava
authors.forename: Claude
authors.initials: C
authors.lastname: Kedinger
authors.forename: Bruno
authors.initials: B
authors.lastname: Chatton
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics* / Q000378:metabolism*; D051696:Activating Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C497105:ATF2 protein, human; C427752:ATF7 protein, human; C000619447:ATF7 protein, mouse; D051698:Activating Transcription Factor 2; D051696:Activating Transcription Factors; D020033:Protein Isoforms; D013912:Threonine; D020928:Mitogen-Activated Protein Kinases