Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo
- *Departments of Biological Chemistry and Molecular Pharmacology and †Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115
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Edited by Peter S. Kim, Merck Research Laboratories, West Point, PA, and approved July 26, 2005 (received for review May 9, 2005)
Abstract
Calcineurin phosphatase activity regulates the nuclear localization of the nuclear factor of activated T cells (NFAT) family of transcription factors during immune challenge. Calcineurin inhibitors, such as the cyclosporin A–cyclophilin A and FK506–FKBP12 complexes, regulate this enzymatic activity noncompetitively by binding at a site distinct from the enzyme active site. A family of endogenous protein inhibitors of calcineurin was recently identified and shown to block calcineurin-mediated NFAT nuclear localization and transcriptional activation. One such inhibitor, Down Syndrome Critical Region 1 (DSCR1), functions in T cell activation, cardiac hypertrophy, and angiogenesis. We have identified a small region of DSCR1 that is a potent inhibitor of calcineurin activity in vitro and in vivo.
Footnotes
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↵ ‡ To whom correspondence may be addressed. E-mail: tome{at}hms.harvard.edu or frank_mckeon{at}hms.harvard.edu.
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Author contributions: B.C., F.M., and T.E. designed research; B.C. and G.G. performed research; B.C., G.G., F.M., and T.E. analyzed data; and B.C., F.M., and T.E. wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: BHK, baby hamster kidney; DSCR1, Down Syndrome Critical Region 1; NFAT, nuclear factor of activated T cells.
- Copyright © 2005, The National Academy of Sciences
