The zinc finger and C-terminal domains of MTA proteins are required for FOG-2-mediated transcriptional repression via the NuRD complex.

Abstract

FOG-2 is a transcriptional co-regulator that is required for cardiac morphogenesis as mice deficient in this factor die during mid-gestation of cardiac malformations. FOG-2 interacts with GATA4 to attenuate GATA4-dependent gene expression. The first 12 amino acids of FOG-2 (the FOG Repression Motif) are necessary to mediate this repression. To determine the mechanism by which the FOG Repression Motif functions, we identified 7 polypeptides from rat cardiac nuclear extracts that co-purified with a GST-FOG-2 fusion protein. All proteins identified are members of the NuRD nucleosome remodeling complex. Using in vitro binding and co-immunoprecipitation assays, we demonstrate that Metastasis-Associated proteins (MTA)-1, 2 and 3 and Retinoblastoma binding proteins RbAp46 and RbAp48 interact with FOG-2, but not with a mutant form of FOG-2 that is unable to repress transcription. Furthermore, we define a novel domain located in the C-terminal portion of MTA-1 that mediates the FOG-2/MTA-1 interaction. We also demonstrate that knockdown of MTA protein expression dramatically impairs the ability of FOG-2 to repress GATA4 activity. Finally, we show that the zinc finger domain of MTA-1 is required for FOG-2-mediated transcriptional repression and that this domain interacts with RbAp46 and RbAp48 subunits of the NuRD complex. Together, these results demonstrate the importance of FOG-2/MTA/RbAp interactions for FOG-2-mediated transcriptional repression and further define the molecular interactions between the FOG Repression Motif and the NuRD complex.

• Authors: Andrea E Roche, Brett J Bassett, Sadhana A Samant, Wei Hong, Gerd A Blobel, Eric C Svensson
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 44 Issue 2 Pg. 352-60 (Feb 2008) ISSN: 1095-8584 [Electronic] England
• PMID: 18067919 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA-Binding Proteins
• Mta1 protein, mouse
• Mta3 protein, mouse
• Neoplasm Proteins
• Protein Subunits
• Repressor Proteins
• Retinoblastoma Protein
• Trans-Activators
• Transcription Factors
• Histone Deacetylases
• Mi-2 Nucleosome Remodeling and Deacetylase Complex

Topics

• Amino Acid Motifs
• Animals
• Chromatography, Affinity
• DNA-Binding Proteins (metabolism)
• Histone Deacetylases (metabolism)
• Mi-2 Nucleosome Remodeling and Deacetylase Complex
• Mice
• NIH 3T3 Cells
• Neoplasm Proteins (chemistry, metabolism)
• Protein Binding
• Protein Structure, Tertiary
• Protein Subunits (metabolism)
• Protein Transport
• Rats
• Repressor Proteins (chemistry, metabolism)
• Retinoblastoma Protein (metabolism)
• Trans-Activators
• Transcription Factors (chemistry, metabolism)
• Transcription, Genetic
• Zinc Fingers