Context-dependent transcriptional cooperation mediated by cardiac transcription factors Csx/Nkx-2.5 and GATA-4

Ichiro Shiojima, Issei Komuro, Toru Oka, Yukio Hiroi, Takehiko Mizuno, Eiki Takimoto, Koshiro Monzen, Ryuichi Aikawa, Hiroshi Akazawa, Tsutomu Yamazaki, Sumiyo Kudoh, Yoshio Yazaki

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Although the cardiac homeobox gene Csx/Nkx-2.5 is essential for normal heart development, little is known about its regulatory mechanisms. In a search for the downstream target genes of Csx/Nkx-2.5, we found that the atrial natriuretic peptide (ANP) gene promoter was strongly transactivated by Csx/Nkx-2.5. Deletion and mutational analyses of the ANP promoter revealed that the Csx/Nkx-2.5-binding element (NKE2) located at -240 was required for high level transactivation by Csx/Nkx-2.5. We also found that Csx/Nkx-2.5 and GATA-4 displayed synergistic transcriptional activation of the ANP promoter, and in contrast to previous reports (Durocher, D, Charton, F., Warren, R., Schwartz, R. J., and Nemer, M. (1997) EMBO J. 16, 5687-5696; Lee, Y., Shioi, T., Kasahara, H., Jobe, S. M., Wiese, R. J., Markham, B., and Izumo, S (1998) Mol. Cell Biol. 18, 3120-3129), this synergism was dependent on binding of Csx/Nkx-2.5 to NKE2, but not on GATA-4-DNA interactions. Although GATA-4 also potentiated the Csx/Nkx-2.5-induced transactivation of the artificial promoter that contains multimerized Csx/Nkx-2.5-binding sites, Csx/Nkx-2.5 reduced the GATA-4-induced transactivation of the GATA-4-dependent promoters. These findings indicate that the cooperative transcriptional regulation mediated by Csx/Nkx-2.5 and GATA-4 is promoter context-dependent and suggest that the complex cis-trans interactions may fine-tune gene expression in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)8231-8239
Number of pages9
JournalJournal of Biological Chemistry
Issue number12
StatePublished - Mar 19 1999
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry

Cite this

Shiojima, I., Komuro, I., Oka, T., Hiroi, Y., Mizuno, T., Takimoto, E., Monzen, K., Aikawa, R., Akazawa, H., Yamazaki, T., Kudoh, S., & Yazaki, Y. (1999). Context-dependent transcriptional cooperation mediated by cardiac transcription factors Csx/Nkx-2.5 and GATA-4. Journal of Biological Chemistry, 274(12), 8231-8239.