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J Biol Chem, Vol. 274, Issue 44, 31543-31552, October 29, 1999

The Homeodomain Transcription Factor NK-4 Acts as either a Transcriptional Activator or Repressor and Interacts with the p300 Coactivator and the Groucho Corepressor

Cheol Yong Choi, Young Mi Lee, Young Ho Kim, Taekyu Park^¶, Byung Hun Jeon, Robert A. Schulz, and Yongsok Kim

From the  Laboratory of Molecular Cardiology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the ^¶ Department of Molecular Biology, Kon Kuk University, Chung Ju, Korea, and the  Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

NK-4 (tinman) encodes an NK-2 class homeodomain transcription factor that is required for development of the Drosophila dorsal mesoderm, including heart. Genetic evidence suggests its important role in mesoderm subdivision, yet the properties of NK-4 as a transcriptional regulator and the mechanism of gene transcription by NK-4 are not completely understood. Here, we describe its properties as a transcription factor and its interaction with the p300 coactivator and the Groucho corepressor. We demonstrate that NK-4 can activate or repress target genes in cultured cells, depending on functional domains that are conserved between Drosophila melanogaster and Drosophila virilis NK-4 genes. Using GAL4-NK-4 fusion constructs, we have mapped a transcriptional activation domain (amino acids 1-110) and repression domains (amino acids 111-188 and the homeodomain) and found an inhibitory function for the homeodomain in transactivation by NK-4. Furthermore, we demonstrate that NK-4-dependent transactivation is augmented by the p300 coactivator and show that NK-4 physically interacts with p300 via the activation domain. In addition, cotransfection experiments indicate that the repressor activity of NK-4 is strongly enhanced by the Groucho corepressor. Using immunoprecipitation and in vitro pull-down assays, we show that NK-4 directly interacts with the Groucho corepressor, for which the homeodomain is required. Together, our results indicate that NK-4 can act as either a transcriptional activator or repressor and provide the first evidence of NK-4 interactions with the p300 coactivator and the Groucho corepressor.

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