A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling

Here we describe a small family of proteins, termed MCIP1 and MCIP2 (for my ocyte-enriched calcineurin interacting protein), that are expressed most ab undantly in striated muscles and that form a physical complex with calcineu rin A. MCIP1 is encoded by DSCR1, a gene located in the Down syndrome criti cal region, Expression of the MCIP family of proteins is up-regulated durin g muscle differentiation, and their forced overexpression inhibits calcineu rin signaling to a muscle-specific target gene in a myocyte cell background . Binding of MCIP1 to calcineurin A requires sequence motifs that resemble calcineurin interacting domains found in NFAT proteins. The inhibitory acti on of MCIP1 involves a direct association with the catalytic domain of calc ineurin, rather than interference with the function of downstream component s of the calcineurin signaling pathway, The interaction between MCIP protei ns and calcineurin may modulate calcineurin-dependent pathways that control hypertrophic growth and selective programs of gene expression in striated muscles.