Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 50, Pages 19637-19642Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0810648105
Keywords
activation domain; CREB-binding protein; dimerization; protein-DNA interactions; TNF
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Funding
- National Institutes of Health Grants [AI-20642, GM-56492, GM-54605]
- American Heart Association
- March of Dimes, Pew Scholars Program in the Biomedical Sciences
- Irma T. Hirschl Trust
- Arthritis National Research Foundation
- National Cancer Institute/National Institutes of Health [P50 CA89520]
- Department of Defense National Defense Science and Engineering
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The transcription factor NFATp integrates multiple signal transduction pathways through coordinate binding with basic-region leucine zipper (bZIP) proteins and other transcription factors. The NFATp monomer, even in the absence of its activation domains, recruits bZIP proteins to canonical NFAT-bZIP composite DNA elements. By contrast, the NFATp dimer and its bZIP partner bind noncooperatively to the NFAT-bZIP element of the tumor necrosis factor (TNF) gene promoter. This observation raises the possibility that the function of the activation domains of NFATp is dimer-specific. Here, we determine the consensus DNA binding site of the NFATp dimer, describe monomer- and dimer-specific NFATp-DNA contact patterns, and demonstrate that NFATp dimerization and dimer-specific activation subdomains are required for transcriptional activation from the TNF NFAT-bZIP element. We also show that these NFATp subdomains interact with the coactivator CBP (CREB-binding protein), which is required for NFATp-dependent TNF gene transcription. Thus, the context-specific function of the activation domains of NFAT can be potentiated by DNA-directed dimerization.
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