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Molecular and Cellular Biology, October 2000, p. 7550-7558, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cardiac Tissue Enriched Factors Serum Response Factor and GATA-4 Are Mutual Coregulators

Narasimhaswamy S. Belaguli,1 Jorge L. Sepulveda,1 Vishal Nigam,1 Frédéric Charron,2 Mona Nemer,2 and Robert J. Schwartz1,*

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030,1 and Laboratoire de Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada H2W 1R72

Received 29 March 2000/Returned for modification 17 May 2000/Accepted 12 June 2000

Combinatorial interaction among cardiac tissue-restricted enriched transcription factors may facilitate the expression of cardiac tissue-restricted genes. Here we show that the MADS box factor serum response factor (SRF) cooperates with the zinc finger protein GATA-4 to synergistically activate numerous myogenic and nonmyogenic serum response element (SRE)-dependent promoters in CV1 fibroblasts. In the absence of GATA binding sites, synergistic activation depends on binding of SRF to the proximal CArG box sequence in the cardiac and skeletal alpha -actin promoter. GATA-4's C-terminal activation domain is obligatory for synergistic coactivation with SRF, and its N-terminal domain and first zinc finger are inhibitory. SRF and GATA-4 physically associate both in vivo and in vitro through their MADS box and the second zinc finger domains as determined by protein A pullout assays and by in vivo one-hybrid transfection assays using Gal4 fusion proteins. Other cardiovascular tissue-restricted GATA factors, such as GATA-5 and GATA-6, were equivalent to GATA-4 in coactivating SRE-dependent targets. Thus, interaction between the MADS box and C4 zinc finger proteins, a novel regulatory paradigm, mediates activation of SRF-dependent gene expression.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6649. Fax: (713) 798-7799. E-mail: schwartz{at}bcm.tmc.edu.

Molecular and Cellular Biology, October 2000, p. 7550-7558, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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