Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo.
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.
Chan
Betty
B
Department of Biological Chemistry, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Greenan
Garrett
G
McKeon
Frank
F
Ellenberger
Tom
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D009124:Muscle Proteins / Q000737:chemistry / Q000494:pharmacology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D014157:Transcription Factors / Q000378:metabolism
D000814:Aniline Compounds; D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009943:Organophosphorus Compounds; D010446:Peptide Fragments; C108612:RCAN1 protein, human; D014157:Transcription Factors; C068798:4-aminophenylphosphate; D019703:Calcineurin