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The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors.

The EMBO journal | Sep 15, 1997

http://www.ncbi.nlm.nih.gov/pubmed/9312027

The tissue-restricted GATA-4 transcription factor and Nkx2-5 homeodomain protein are two early markers of precardiac cells. Both are essential for heart formation, but neither can initiate cardiogenesis. Overexpression of GATA-4 or Nkx2-5 enhances cardiac development in committed precursors, suggesting each interacts with a cardiac cofactor. We tested whether GATA-4 and Nkx2-5 are cofactors for each other by using transcription and binding assays with the cardiac atrial natriuretic factor (ANF) promoter_the only known target for Nkx2-5. Co-expression of GATA-4 and Nkx2-5 resulted in synergistic activation of the ANF promoter in heterologous cells. The synergy involves physical Nkx2-5-GATA-4 interaction, seen in vitro and in vivo, which maps to the C-terminal zinc finger of GATA-4 and a C-terminus extension; similarly, a C-terminally extended homeodomain of Nkx2-5 is required for GATA-4 binding. Structure/function studies suggest that binding of GATA-4 to the C-terminus autorepressive domain of Nkx2-5 may induce a conformational change that unmasks Nkx2-5 activation domains. GATA-6 cannot substitute for GATA-4 for interaction with Nkx2-5. This interaction may impart functional specificity to GATA factors and provide cooperative crosstalk between two pathways critical for early cardiogenesis. Given the co-expression of GATA proteins and NK2 class members in other tissues, the GATA/Nkx partnership may represent a paradigm for transcription factor interaction during organogenesis.

Pubmed ID: 9312027 RIS Download

Mesh terms: Animals | Atrial Natriuretic Factor | Base Sequence | Caenorhabditis elegans | Cell Line | Conserved Sequence | DNA-Binding Proteins | Drosophila | GATA4 Transcription Factor | HeLa Cells | Heart | Homeodomain Proteins | Humans | Molecular Sequence Data | Myocardium | Promoter Regions, Genetic | Recombinant Fusion Proteins | Sequence Alignment | Sequence Homology, Nucleic Acid | Transcription Factors | Transcription, Genetic | Transfection | Vertebrates | Xenopus Proteins

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Associated grants

  • Agency: PHS HHS, Id: R0150422

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