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Gene Review

RCAN1  -  regulator of calcineurin 1

Homo sapiens

Synonyms: ADAPT78, Adapt78, CSP1, Calcipressin-1, DSC1, ...
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Disease relevance of DSCR1

  • Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells [1].
  • Under in vivo conditions, overexpression of DSCR-1 reduced vascular density in matrigel plugs and melanoma tumor growth in mice [2].
  • All three segments appear to include three functional members of three different gene families: DSCR1-like (Down Syndrome Candidate Region 1-like), CLIC, and AML/Runt (Acute Myeloid Leukemia/Runt) [3].
  • In the present study, we show that expression of MCIP1 is regulated by calcineurin activity in hearts of mice with cardiac hypertrophy, as well as in cultured skeletal myotubes [4].
  • To elucidate the molecular basis of these anti-inflammatory effects, we analyzed the role of DSCR1 in the regulation of NF-kappaB transactivation using glioblastoma cells stably transfected with DSCR1.4 or its truncation mutants (DSCR1.4-(1-133) and DSCR1.4-(134-197)) [5].

Psychiatry related information on DSCR1

  • Structural characteristics, together with its particular expression in brain and heart, encourage us to suggest that the overexpression of DSCR1 may be involved in the pathogenesis of Down syndrome, in particular mental retardation and/or cardiac defects [6].
  • Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease [7].

High impact information on DSCR1


Chemical compound and disease context of DSCR1


Biological context of DSCR1


Anatomical context of DSCR1

  • Thus, the negative regulatory feedback loop between DSCR1 and CnA signaling in endothelial cells identified may represent a potential molecular mechanism underlying the frequently transient expression of inflammatory genes following activation of endothelial cells [1].
  • Consistent with an antagonistic function on calcineurin (CnA) signaling, expression of DSCR1 in endothelial cells blocked dephosphorylation, nuclear translocation, and activity of nuclear factor of activated T cell (NFAT), a transcription factor involved in mediating CnA signaling [1].
  • 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 [17].
  • DSCR1 is highly expressed in human brain and heart, and increased expression in the brains of young rats compared with adults suggests a role for DSCR1 during central nervous system development [6].
  • 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 [18].

Associations of DSCR1 with chemical compounds

  • We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-alpha, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca(2+) chelator [19].
  • These results suggest that DSCR1 is involved in angiogenesis by regulating adhesion and migration of ECs via the interaction with integrin alphavbeta3 [20].
  • Moreover, VEGF-stimulated induction of DSCR1 was blocked by anti-VEGF receptor-2 monoclonal antibody (mAb), or the specific calcineurin inhibitors cyclosporin A and FK506 [20].
  • Recently the DSCR1 (Adapt78) gene product was discovered to be an inhibitor of the serine/threonine phosphatase, calcineurin, and its signaling pathways [7].
  • In contrast, expression of MCIP2 in the heart is not altered by activated calcineurin but responds to thyroid hormone, which has no effect on MCIP1 [4].

Physical interactions of DSCR1

  • We determined two Raf-1 binding regions in DSCR1; one in the N-terminus and the other in the C-terminus regions [21].

Regulatory relationships of DSCR1


Other interactions of DSCR1

  • These data indicate an entirely new role for a DSCR1-like family gene, suggesting a possible involvement of DSCR1L2 in cardiac contraction [16].
  • Transient expression of DSCR1 attenuated inflammatory marker genes such as tissue factor (TF), E-selectin, and Cox-2, identifying a previously unknown regulatory role for DSCR1 in activated endothelial cells [1].
  • Constitutive expression of DSCR-1 in endothelial cells markedly impaired NF-ATc nuclear localization, proliferation, and tube formation [2].
  • Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators [19].
  • Using multiplex semi-quantitative fluorescent PCR, we amplified the ten exons of SLC3A1 together with exon 5 of DSCR1 (located on chromosome 21) as a double-dose control gene [24].

Analytical, diagnostic and therapeutic context of DSCR1


  1. Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Hesser, B.A., Liang, X.H., Camenisch, G., Yang, S., Lewin, D.A., Scheller, R., Ferrara, N., Gerber, H.P. Blood (2004) [Pubmed]
  2. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. Minami, T., Horiuchi, K., Miura, M., Abid, M.R., Takabe, W., Noguchi, N., Kohro, T., Ge, X., Aburatani, H., Hamakubo, T., Kodama, T., Aird, W.C. J. Biol. Chem. (2004) [Pubmed]
  3. Segmental paralogy in the human genome: a large-scale triplication on 1p, 6p, and 21q. Strippoli, P., D'Addabbo, P., Lenzi, L., Giannone, S., Canaider, S., Casadei, R., Vitale, L., Carinci, P., Zannotti, M. Mamm. Genome (2002) [Pubmed]
  4. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Yang, J., Rothermel, B., Vega, R.B., Frey, N., McKinsey, T.A., Olson, E.N., Bassel-Duby, R., Williams, R.S. Circ. Res. (2000) [Pubmed]
  5. Down Syndrome Candidate Region 1 Increases the Stability of the I{kappa}B{alpha} Protein: IMPLICATIONS FOR ITS ANTI-INFLAMMATORY EFFECTS. Kim, Y.S., Cho, K.O., Lee, H.J., Kim, S.Y., Sato, Y., Cho, Y.J. J. Biol. Chem. (2006) [Pubmed]
  6. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Fuentes, J.J., Pritchard, M.A., Planas, A.M., Bosch, A., Ferrer, I., Estivill, X. Hum. Mol. Genet. (1995) [Pubmed]
  7. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. Ermak, G., Morgan, T.E., Davies, K.J. J. Biol. Chem. (2001) [Pubmed]
  8. GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Hilioti, Z., Gallagher, D.A., Low-Nam, S.T., Ramaswamy, P., Gajer, P., Kingsbury, T.J., Birchwood, C.J., Levchenko, A., Cunningham, K.W. Genes Dev. (2004) [Pubmed]
  9. A conserved family of calcineurin regulators. Kingsbury, T.J., Cunningham, K.W. Genes Dev. (2000) [Pubmed]
  10. Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo. Chan, B., Greenan, G., McKeon, F., Ellenberger, T. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning: implications for mental retardation. Chang, K.T., Shi, Y.J., Min, K.T. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Rothermel, B.A., McKinsey, T.A., Vega, R.B., Nicol, R.L., Mammen, P., Yang, J., Antos, C.L., Shelton, J.M., Bassel-Duby, R., Olson, E.N., Williams, R.S. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  13. Application of Alu-splice PCR on chromosome 21: DSCR1 and Intersectin. Fuentes, J.J., Dierssen, M., Pucharcós, C., Fillat, C., Casas, C., Estivill, X., Pritchard, M. J. Neural Transm. Suppl. (1999) [Pubmed]
  14. Characterization of two labor-induced genes, DSCR1 and TCTE1L, in the pregnant ovine myometrium. Wu, W.X., Ma, X.H., Zhang, Q., Chakrabarty, K., Nathanielsz, P.W. J. Endocrinol. (2003) [Pubmed]
  15. The murine DSCR1-like (Down syndrome candidate region 1) gene family: conserved synteny with the human orthologous genes. Strippoli, P., Petrini, M., Lenzi, L., Carinci, P., Zannotti, M. Gene (2000) [Pubmed]
  16. Proteins encoded by human Down syndrome critical region gene 1-like 2 (DSCR1L2) mRNA and by a novel DSCR1L2 mRNA isoform interact with cardiac troponin I (TNNI3). Canaider, S., Facchin, F., Griffoni, C., Casadei, R., Vitale, L., Lenzi, L., Frabetti, F., D'Addabbo, P., Carinci, P., Zannotti, M., Strippoli, P. Gene (2006) [Pubmed]
  17. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. Rothermel, B., Vega, R.B., Yang, J., Wu, H., Bassel-Duby, R., Williams, R.S. J. Biol. Chem. (2000) [Pubmed]
  18. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Fuentes, J.J., Genescà, L., Kingsbury, T.J., Cunningham, K.W., Pérez-Riba, M., Estivill, X., de la Luna, S. Hum. Mol. Genet. (2000) [Pubmed]
  19. VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis? Yao, Y.G., Duh, E.J. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  20. Down syndrome candidate region 1,a downstream target of VEGF, participates in endothelial cell migration and angiogenesis. Iizuka, M., Abe, M., Shiiba, K., Sasaki, I., Sato, Y. J. Vasc. Res. (2004) [Pubmed]
  21. Raf-1 is a binding partner of DSCR1. Cho, Y.J., Abe, M., Kim, S.Y., Sato, Y. Arch. Biochem. Biophys. (2005) [Pubmed]
  22. Thrombin-induced autoinhibitory factor, Down syndrome critical region-1, attenuates NFAT-dependent vascular cell adhesion molecule-1 expression and inflammation in the endothelium. Minami, T., Miura, M., Aird, W.C., Kodama, T. J. Biol. Chem. (2006) [Pubmed]
  23. adapt78, a stress-inducible mRNA, is related to the glucose-regulated protein family of genes. Leahy, K.P., Davies, K.J., Dull, M., Kort, J.J., Lawrence, K.W., Crawford, D.R. Arch. Biochem. Biophys. (1999) [Pubmed]
  24. Detection of two novel large deletions in SLC3A1 by semi-quantitative fluorescent multiplex PCR. Purroy, J., Bisceglia, L., Jaeken, J., Gasparini, P., Palacín, M., Nunes, V. Hum. Mutat. (2000) [Pubmed]
  25. Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Fuentes, J.J., Pritchard, M.A., Estivill, X. Genomics (1997) [Pubmed]
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