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 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.
Rothermel
B
B
Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8573, USA.
Vega
R B
RB
Yang
J
J
Wu
H
H
Bassel-Duby
R
R
Williams
R S
RS
D017398:Alternative Splicing; D000818:Animals; D065095:Calcineurin Inhibitors; D020134:Catalytic Domain; D002451:Cell Compartmentation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores / Q000494:pharmacology; D064326:MEF2 Transcription Factors; D051379:Mice; D005810:Multigene Family; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D011485:Protein Binding; D011506:Proteins; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; C486303:Dscr1l1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D064326:MEF2 Transcription Factors; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D011506:Proteins; C108612:RCAN1 protein, human; C100360:RCAN2 protein, human; D014157:Transcription Factors; D013755:Tetradecanoylphorbol Acetate