title: Convergence of protein kinase C and JAK-STAT signaling on transcription factor GATA-4.
abstract: Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this process; however, which of these directly link receptor activation to transcriptional regulation remains undefined. We used the atrial natriuretic factor (ANF) gene (NPPA) as a marker to elucidate the signaling cascades involved in AII transcriptional responses. We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy. This response maps to STAT and GATA binding sites, and the two elements transcriptionally cooperate to mediate signaling through the JAK-STAT and protein kinase C (PKC)-GATA-4 pathways. PKC phosphorylation enhances GATA-4 DNA binding activity, and STAT-1 functionally and physically interacts with GATA-4 to synergistically activate AII and other growth factor-inducible promoters. Moreover, GATA factors are able to recruit STAT proteins to target promoters via GATA binding sites, which are sufficient to support synergy. Thus, STAT proteins can act as growth factor-inducible coactivators of tissue-specific transcription factors. Interactions between STAT and GATA proteins may provide a general paradigm for understanding cell specificity of cytokine and growth factor signaling.
authors.affiliation: Unité de Recherche en Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, 110, Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Anne
authors.initials: A
authors.lastname: Aries
authors.forename: Hiba
authors.initials: H
authors.lastname: Komati
authors.forename: Chantal
authors.initials: C
authors.lastname: Lefebvre
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001665:Binding Sites; D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050991:GATA4 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008957:Models, Genetic; D032383:Myocytes, Cardiac / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D050991:GATA4 Transcription Factor; D050791:STAT Transcription Factors; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D004247:DNA; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases