Recruitment of the coactivator CREB-binding protein (CBP) to transcription factors is important for gene expression. Various regions of CBP such as the KIX and CH3 domains have been shown to interact with numerous transcription factors. The NFAT group of transcription factors is involved in multiple biological processes. NFATc4/NFAT3 has been proposed to play an important role in heart hypertrophy, adipocyte differentiation, and learning and memory. We demonstrate here that two transactivation

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... omains, located at the NH 2 and COOH termini of NFATc4, are critical for interacting with CBP. Each transactivation domain interacts with a distinct region of the CBP protein (the KIX and CH3 domains). Binding of CBP potentiates NFATc4-mediated transcription activity. Both transactivation domains of NFATc4 are required for CBP function. Removal of either NFATc4 transactivation domain abolishes CBP potentiation. Conversely, mutation of the KIX or CH3 domain prevents CBP-mediated potentiation of NFATc4 transcription activation. These data demonstrate that formation of a functional NFATc4⅐CBP transcription complex requires interactions at two distinct sites.