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

Juan J. Fuentes, Lali Genescà, Tami J. Kingsbury, Kyle W. Cunningham, Mercè Pérez-Riba, Xavier P. Estivill, Susana De La Luna

Research output: Contribution to journalArticle

368 Citations (Scopus)

Abstract

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 Ca2+/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.

Original languageEnglish
Pages (from-to)1681-1690
Number of pages10
JournalHuman Molecular Genetics
Volume9
Issue number11
Publication statusPublished - 1 Jul 2000
Externally publishedYes

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Calcineurin
Down Syndrome
Chromosomes, Human, Pair 21
Catalytic Domain
Physiological Phenomena
Genes
Congenital Heart Defects
Phosphoprotein Phosphatases
Immune System Diseases
Brain
Calmodulin
Calcineurin Inhibitors
Intellectual Disability
Myocardium
Alzheimer Disease
Skeletal Muscle
Proteins
Fetus

ASJC Scopus subject areas

  • Genetics

Cite this

Fuentes, J. J., Genescà, L., Kingsbury, T. J., Cunningham, K. W., Pérez-Riba, M., Estivill, X. P., & De La Luna, S. (2000). DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Human Molecular Genetics, 9(11), 1681-1690.

DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. / Fuentes, Juan J.; Genescà, Lali; Kingsbury, Tami J.; Cunningham, Kyle W.; Pérez-Riba, Mercè; Estivill, Xavier P.; De La Luna, Susana.

In: Human Molecular Genetics, Vol. 9, No. 11, 01.07.2000, p. 1681-1690.

Research output: Contribution to journalArticle

Fuentes, JJ, Genescà, L, Kingsbury, TJ, Cunningham, KW, Pérez-Riba, M, Estivill, XP & De La Luna, S 2000, 'DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways', Human Molecular Genetics, vol. 9, no. 11, pp. 1681-1690.
Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill XP et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Human Molecular Genetics. 2000 Jul 1;9(11):1681-1690.
Fuentes, Juan J. ; Genescà, Lali ; Kingsbury, Tami J. ; Cunningham, Kyle W. ; Pérez-Riba, Mercè ; Estivill, Xavier P. ; De La Luna, Susana. / DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. In: Human Molecular Genetics. 2000 ; Vol. 9, No. 11. pp. 1681-1690.
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