DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways

• Published in: Human molecular genetics 2000-07, Vol.9 (11), p.1681-1690
• Main Authors: FUENTES, J. J, GENESCA, L, KINGSBURY, T. J, CUNNINGHAM, K. W, PEREZ-RIBA, M, ESTIVILL, X, DE LA LUNA, S
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Binding Sites; Biological and medical sciences; Calcineurin - metabolism; Calcineurin - physiology; calcineurin A; Calcineurin Inhibitors; Calcium - pharmacology; Cell Nucleus - metabolism; chromosome 21; Chromosome aberrations; COS Cells; DNA-Binding Proteins - metabolism; Down Syndrome - genetics; DSCR1 protein; DSCR1L2 protein; Gene Expression Regulation - drug effects; Humans; Intracellular Signaling Peptides and Proteins; Medical genetics; Medical sciences; Molecular Sequence Data; Muscle Proteins - chemistry; Muscle Proteins - genetics; Muscle Proteins - metabolism; NFATC Transcription Factors; Nuclear Proteins; Protein Binding; protein phosphatase PP2B; Protein Structure, Tertiary; RNA - drug effects; RNA - genetics; RNA - metabolism; Sequence Homology, Amino Acid; Signal Transduction; Transcription Factors - metabolism; Transcriptional Activation; Tumor Cells, Cultured; ZAKI-4 protein
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.11.1681

Down syndrome is one of the major causes of mental retardation and congenital heart malformations. Other common clinical features of Down syndrome include gastrointestinal anomalies, immune system defects and Alzheimer's disease pathological and neurochemical changes. The most likely consequence of the presence of three copies of chromosome 21 is the overexpression of its resident genes, a fact which must underlie the pathogenesis of the abnormalities that occur in Down syndrome. Here we show that DSCR1, the product of a chromosome 21 gene highly expressed in brain, heart and skeletal muscle, is overexpressed in the brain of Down syndrome fetuses, and interacts physically and functionally with calcineurin A, the catalytic subunit of the Ca(2+)/calmodulin-dependent protein phosphatase PP2B. The DSCR1 binding region in calcineurin A is located in the linker region between the calcineurin A catalytic domain and the calcineurin B binding domain, outside of other functional domains previously defined in calcineurin A. DSCR1 belongs to a family of evolutionarily conserved proteins with three members in humans: DSCR1, ZAKI-4 and DSCR1L2. We further demonstrate that overexpression of DSCR1 and ZAKI-4 inhibits calcineurin-dependent gene transcription through the inhibition of NF-AT translocation to the nucleus. Together, these results suggest that members of this newly described family of human proteins are endogenous regulators of calcineurin-mediated signaling pathways and as such, they may be involved in many physiological processes.