A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling

Abstract

Here we describe a small family of proteins, termed MCIP1 and MCIP2 (for myocyte-enriched calcineurin interacting protein), that are expressed most abundantly in striated muscles and that form a physical complex with calcineurin A. MCIP1 is encoded by DSCR1, a gene located in the Down syndrome critical region. Expression of the MCIP family of proteins is up-regulated during muscle differentiation, and their forced overexpression inhibits calcineurin 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 action of MCIP1 involves a direct association with the catalytic domain of calcineurin, rather than interference with the function of downstream components of the calcineurin signaling pathway. The interaction between MCIP proteins and calcineurin may modulate calcineurin-dependent pathways that control hypertrophic growth and selective programs of gene expression in striated muscles.Calcineurin is a serine/threonine protein phosphatase that plays a pivotal role in developmental and homeostatic regulation of a wide variety of cell types (1, 2). The interaction of calcineurin with transcription factors of the NFAT 1 family following activation of the T cell receptor in leukocytes provides the best characterized example of how calcineurin regulates gene expression (3). Changes in intracellular calcium promote binding of Ca 2ϩ /calmodulin to the catalytic subunit of calcineurin (CnA), thereby displacing an autoinhibitory region and allowing access of protein substrates to the catalytic domain. Dephosphorylation of NFAT by activated calcineurin promotes its translocation from the cytoplasm to the nucleus, where NFAT binds DNA cooperatively with an AP1 heterodimer to activate transcription of genes encoding cytokines such as IL-2. This basic model of NFAT activation has been shown to transduce Ca 2ϩ signals via calcineurin in many cell types and to control transcription of diverse sets of target genes unique to each cellular environment (4). In each case, NFAT acts cooperatively with other transcription factors that include proteins of the AP1 (3), cMAF (5), GATA (6 -8), or MEF2 (9 -12) families. In addition to T cell activation, cellular responses controlled by calcineurin signaling include synaptic plasticity (11,13,14) and apoptosis (15,16).Recent studies of calcineurin signaling in striated myocytes of heart and skeletal muscle have expanded the scope of important physiological and pathological events controlled by this ubiquitously expressed protein. Forced expression of a constitutively active form of calcineurin in hearts of transgenic mice promotes cardiac hypertrophy that progresses to dilated cardiomyopathy, heart failure, and death, in a manner that recapitulates features of human disease (7). Moreover, hypertrophy and heart failure in these animals, and in certain other animal models of cardiomyopathy, are prevented by administration of the calcin...

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

“…Briefly, muscle samples (~50-75 mg), were homogenized in 1 ml of ice-cold lysis buffer (10 mM NaCl, 1.5 mM MgCl 2 , 20 mM HEPES at pH 7.4, 20% glycerol, 0.1% Triton X-100, and 1 mM dithioreitol) to obtain cytoplasmic protein extracts according to the methods of Rothermel et al [30]. Muscle homogenates were centrifuged at 3000 rpm for 5-min at 4°C.…”

Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells

“…It is known that the phosphorylated form of NFATc, which is retained in the cytoplasm, enters the nucleus through its dephosphorylation by Ca 2+ /calcineurin and activates the transcription (Crabtree 1999). In this activation process, DSCR1 inhibits calcineurin and thereby suppresses dephosphorylation and nuclear entry of NFATc (Rothermel et al 2000). On the other hand, nuclear export of NFATc is accelerated upon its priming phosphorylation of the serine/proline repeats by DYRK1A (Arron et al 2006;Gwack et al 2006) and subsequent phosphorylation by GSK3 (Graef et al 1999).…”

“…Also, Dyrk1a transgenic mice display alteration of brain size and neuronal density in the cerebral cortex (Guedj et al 2012). Dscr1 also lies within the centromeric border of the DSCR, encodes for an inhibitor of protein phosphatase calcineurin 1, and often is referred to as Rcan1 (regulator of calcineurin 1) (Rothermel et al 2000). Like DYRK1A, DSCR1 is overexpressed in fetal and adult DS brains (Fuentes et al 2000), but its role in CNS development is incompletely understood.…”

Effect of Moderate Acute Exercise on Expression of mRNA Involved in the Calcineurin Signaling Pathway in Human Skeletal Muscle

“…Then, NFAT activates the expression of target genes in combination with myocyte specific enhancer factor 2 (MEF2) (5, 6) and activator protein 1 (AP-1) (4, 7). In addition, the activity of calcineurin is negatively regulated by myocyte-enriched calcineurin-interacting protein 1 (MCIP1), which directly binds to calcineurin (8).…”